Cyclopropyl amide derivatives

ABSTRACT

Disclosed herein is at least one cyclopropyl amide derivative, at least one pharmaceutical composition comprising at least one cyclopropyl amide derivative disclosed herein, and at least one method of using at least one cyclopropyl amide derivative disclosed herein for treating at least one histamine H3 receptor associated condition therewith.

Disclosed herein is at least one cyclopropyl amide derivative, at leastone pharmaceutical composition comprising at least one cyclopropyl amidederivative disclosed herein, and at least one method of using at leastone cyclopropyl amide derivative disclosed herein for treating at leastone histamine H3 receptor associated condition therewith.

The histamine H3 receptor is of current interest in developing newmedicaments. The H3 receptor is a presynaptic autoreceptor located bothin the central and peripheral nervous systems, the skin, and in organs,such as, for example, the lung, the intestine, probably the spleen, andthe gastrointestinal tract. Recent evidence suggests the H3 receptor hasintrinsic, constitutive activity in vitro as well as in vivo (i.e., itis active in the absence of an agonist). Compounds acting as inverseagonists can inhibit this activity. The histamine H3 receptor has beenshown to regulate the release of histamine and also of otherneurotransmitters, such as, for example, serotonin and acetylcholine.Some histamine H3 ligands, such as, for example, a histamine H3 receptorantagonist or inverse agonist may increase the release ofneurotransmitters in the brain, whereas other histamine H3 ligands, suchas, for example, histamine H3 receptor agonists may inhibit thebiosynthesis of histamine, as well as, inhibit the release ofneurotransmitters. This suggests that histamine H3 receptor agonists,inverse agonists, and antagonists could mediate neuronal activity. As aresult, efforts have been undertaken to develop new therapeutics thattarget the histamine H3 receptor.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows an X-ray powder diffraction (XRPD) pattern for Example 35(Crystalline Form I).

Described herein are compounds of formula I, or enantiomers ordiastereomers thereof, or pharmaceutically acceptable salts of formula Ior enantiomers or diastereomers thereof, or mixtures thereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ are each independently selected fromH and C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—(C₁-C₃alkyl)-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —(C₁-C₃alkyl)-(6-membered heteroaryl containingat least one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹²and the N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy; and

provided:

-   -   i) at least one of R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ is a        C₁-C₃alkyl;    -   ii) formula I is not

-   -    when R¹ is a —C(═O)NR¹¹R¹² group meta-attached to the phenyl,        R² is isopropyl, and R¹¹ and R¹² are H; and    -   iii) formula I is not in the cis configuration at the        cyclopropane.

Further described herein are compounds according to formula I, ordiastereomers or enantiomers thereof, or pharmaceutically acceptablesalts of formula I or diastereomers or enantiomers thereof, or mixturesthereof for use as a medicament.

Even further described herein is the use of compounds of formula I, ordiastereomers or enantiomers thereof, or pharmaceutically acceptablesalts of formula I or diastereomers or enantiomers thereof, or mixturesthereof in the manufacture of a medicament for the therapy of at leastone disorder selected from cognitive deficit in schizophrenia,narcolepsy, obesity, attention deficit hyperactivity disorder, pain, andAlzheimer's disease.

Still further described herein is the use of compounds of formula I, ordiastereomers or enantiomers thereof, or pharmaceutically acceptablesalts of formula I or diastereomers or enantiomers thereof, or mixturesthereof in the manufacture of a medicament for the therapy of at leastone disorder selected from cognitive deficit in schizophrenia,narcolepsy, obesity, attention deficit hyperactivity disorder, pain, andAlzheimer's disease.

Yet even further described herein is a pharmaceutical compositioncomprising at least one compound according to formula I, ordiastereomers or enantiomers thereof, or pharmaceutically acceptablesalts of formula I or diastereomers or enantiomers thereof, or mixturesthereof and a pharmaceutically acceptable carrier and/or diluent.

Still even further described herein is a method for treating at leastone disorder selected from cognitive deficit in schizophrenia,narcolepsy, obesity, attention deficit hyperactivity disorder, pain, andAlzheimer's disease in a warm-blooded animal, comprising administeringto said animal in need of such treatment a therapeutically effectiveamount of at least one compound according to formula I, or diastereomersor enantiomers thereof, or pharmaceutically acceptable salts of formulaI or diastereomers or enantiomers thereof, or mixtures thereof.

Still yet even further described herein is a method for treating adisorder in which modulating the histamine H3 receptor is beneficialcomprising administering to a warm-blooded animal in need of suchtreatment a therapeutically effective amount of at least one compoundaccording to formula I, or diastereomers or enantiomers thereof, orpharmaceutically acceptable salts of formula I or diastereomers orenantiomers thereof, or mixtures thereof.

The features and advantages of the invention may be more readilyunderstood by those of ordinary skill in the art upon reading thefollowing detailed description. It is to be appreciated that certainfeatures of the invention that are, for clarity reasons, described aboveand below in the context of separate embodiments, may also be combinedto form a single embodiment. Conversely, various features of theinvention that are, for brevity reasons, described in the context of asingle embodiment, may also be combined so as to form sub-combinationsthereof.

Unless specifically stated otherwise herein, references made in thesingular may also include the plural. For example, “a” and “an” mayrefer to either one, or one or more.

Embodiments identified herein as exemplary are intended to beillustrative and not limiting.

Unless otherwise indicated, any heteroatom with unsatisfied valences isassumed to have hydrogen atoms sufficient to satisfy the valences.

The definitions set forth herein take precedence over definitions setforth in any patent, patent application, and/or patent applicationpublication incorporated herein by reference.

Definitions of terms used in describing the invention are set forthhereinbelow. Unless otherwise indicated, the initial definition providedfor a group or term applies each time such group or term is usedindividually or as part of another group.

Throughout the specification, groups and substituents thereof may bechosen by one skilled in the field to provide stable moieties andcompounds.

The term “C_(m)-C_(n)” or “C_(m)-C_(n) group” used alone or as a prefix,refers to any group having m to n carbon atoms. For example, the term“C₁-C₄alkyl” refers to an alkyl group containing 1, 2, 3, or 4 carbonatoms.

The terms “alkyl” and “alk” refer to a straight or branched chain alkane(hydrocarbon) radical containing from 1 to 12 carbon atoms. Exemplary“alkyl” and “alk” groups include, but are not limited to, for example,methyl; ethyl; propyl; isopropyl; 1-methylpropyl; n-butyl, t-butyl;isobutyl; pentyl; hexyl; isohexyl; heptyl; 4,4-dimethylpentyl;diethylpentyl; octyl; 2,2,4-trimethylpentyl; nonyl; decyl; undecyl; anddodecyl.

The term “hydrocarbon” refers to a chemical structure comprising onlycarbon and hydrogen atoms.

The term “hydrocarbon radical” refers to a hydrocarbon that has had atleast one hydrogen removed therefrom.

The term “aryl” refers to monocyclic or bicyclic aromatic hydrocarbonrings having from 6 to 12 carbon atoms in the ring portion. Exemplaryaryl groups include but are not limited to, for example, phenyl;phen-1-yl-2-yl; phen-1-yl-3-yl; phen-1-yl-4-yl; phen-1-yl-5-yl;phen-1-yl-6-yl; naphthalenyl; naphthalen-1-yl-2-yl;naphthalen-1-yl-3-yl; naphthalen-1-yl-4-yl; naphthalen-1-yl-5-yl;naphthalen-1-yl-6-yl; naphthalen-1-yl-7-yl; naphthalen-1-yl-8-yl;naphthalen-2-yl-3-yl; naphthalen-2-yl-4-yl; naphthalen-2-yl-5-yl;naphthalen-2-yl-6-yl; naphthalen-2-yl-7-yl; naphthalen-2-yl-8-yl;naphthalen-3-yl-4-yl; naphthalen-3-yl-5-yl; naphthalen-3-yl-6-yl;naphthalen-3-yl-7-yl; naphthalen-3-yl-8-yl; naphthalen-4-yl-5-yl;naphthalen-4-yl-6-yl; naphthalen-4-yl-7-yl; naphthalen-4-yl-8-yl;naphthalen-5-yl-6-yl; naphthalen-5-yl-7-yl; naphthalen-5-yl-8-yl;naphthalen-6-yl-7-yl; naphthalen-6-yl-8-yl; naphthalen-7-yl-8-yl;biphenyl; biphenyl-2-yl; biphenyl-3-yl; biphenyl-4-yl; biphenyl-5-yl;biphenyl-6-yl; and diphenyl. When two aromatic rings are present, thearomatic rings of the aryl group may either be joined at a single point(e.g., biphenyl), or be fused (e.g., naphthalenyl). Unless reference ismade to a specific point of attachment, e.g., as in phen-1-yl-2-yl,naphthalen-1-yl-6-yl, and biphenyl-3-yl, it is intended that such arylgroups can be bonded to at least one other moiety at any available pointof attachment.

The term “heteroaryl” refers to aromatic cyclic groups, such as, forexample, 5- to 6-membered monocyclic ring systems having at least oneheteroatom selected from O, N and S in at least one carbonatom-containing ring. The carbon atom-containing ring may contain 1, 2,3, or 4 heteroatom(s) selected from nitrogen, oxygen, and sulfur. Theheteroaryl group may be attached to another moiety at any availablepoint of attachment.

Exemplary monocyclic heteroaryl groups include, but are not limited to,for example, pyrazolyl; pyrazol-1-yl; pyrazol-2-yl; pyrazol-3-yl;pyrazol-4-yl; pyrazol-5-yl; pyrazolylyl; pyrazol-1-yl-2-yl;pyrazol-1-yl-3-yl; pyrazol-1-yl-4-yl; pyrazol-1-yl-5-yl;pyrazol-2-yl-3-yl; pyrazol-2-yl-4-yl; pyrazol-2-yl-5-yl;pyrazol-3-yl-4-yl; pyrazol-3-yl-5-yl; pyrazol-4-yl-5-yl; imidazolyl;imidazol-1-yl; imidazol-2-yl; imidazol-3-yl; imidazol-4-yl;imidazol-5-yl; imidazolylyl; imidazol-1-yl-2-yl; imidazol-1-yl-3-yl;imidazol-1-yl-4-yl; imidazol-1-yl-5-yl; imidazol-2-yl-3-yl;imidazol-2-yl-4-yl; imidazol-2-yl-5-yl; imidazol-3-yl-4-yl;imidazol-3-yl-5-yl; imidazol-4-yl-5-yl; triazolyl; triazol-1-yl;triazol-2-yl; triazol-3-yl; triazol-4-yl; triazol-5-yl; triazolylyl;triazol-1-yl-2-yl; triazol-1-yl-3-yl; triazol-1-yl-4-yl;triazol-1-yl-5-yl; triazol-2-yl-3-yl; triazol-2-yl-4-yl;triazol-2-yl-5-yl; triazol-3-yl-4-yl; triazol-3-yl-5-yl;triazol-4-yl-5-yl; oxazolyl; oxazol-2-yl; oxazol-3-yl; oxazol-4-yl;oxazol-5-yl; oxazolylyl; oxazol-2-yl-3-yl; oxazol-2-yl-4-yl;oxazol-2-yl-5-yl; oxazol-3-yl-4-yl; oxazol-3-yl-5-yl; oxazol-4-yl-5-yl;furyl; fur-2-yl; fur-3-yl; fur-4-yl; fur-5-yl; furylyl; fur-2-yl-3-yl;fur-2-yl-4-yl; fur-2-yl-5-yl; fur-3-yl-4-yl; fur-3-yl-5-yl;fur-4-yl-5-yl; thiazolyl; thiazol-1-yl; thiazol-2-yl; thiazol-3-yl;thiazol-4-yl; thiazol-5-yl; thiazolylyl; thiazol-1-yl-2-yl;thiazol-1-yl-3-yl; thiazol-1-yl-4-yl; thiazol-1-yl-5-yl;thiazol-2-yl-3-yl; thiazol-2-yl-4-yl; thiazol-2-yl-5-yl;thiazol-3-yl-4-yl; thiazol-3-yl-5-yl; thiazol-4-yl-5-yl; isoxazolyl;isoxazol-2-yl; isoxazol-3-yl; isoxazol-4-yl; isoxazol-5-yl;isoxazol-2-yl-3-yl; isoxazol-2-yl-4-yl; isoxazol-2-yl-5-yl;isoxazol-3-yl-4-yl; isoxazol-3-yl-5-yl; isoxazol-4-yl-5-yl; pyridyl;pyrid-1-yl; pyrid-2-yl; pyrid-3-yl; pyrid-4-yl; pyrid-5-yl; pyrid-6-yl;pyridylyl; pyrid-1-yl-2-yl; pyrid-1-yl-3-yl; pyrid-1-yl-4-yl;pyrid-1-yl-5-yl; pyrid-1-yl-6-yl; pyrid-2-yl-3-yl; pyrid-2-yl-4-yl;pyrid-2-yl-5-yl; pyrid-2-yl-6-yl; pyrid-3-yl-4-yl; pyrid-3-yl-5-yl;pyrid-3-yl-6-yl; pyrid-4-yl-5-yl; pyrid-4-yl-6-yl; pyrid-5-yl-6-yl;pyridazinyl; pyridazin-1-yl; pyridazin-2-yl; pyridazin-3-yl;pyridazin-4-yl; pyridazin-5-yl; pyridazin-6-yl; pyridazinylyl;pyridazin-1-yl-2-yl; pyridazin-1-yl-3-yl; pyridazin-1-yl-4-yl;pyridazin-1-yl-5-yl; pyridazin-1-yl-6-yl; pyridazin-2-yl-3-yl;pyridazin-2-yl-4-yl; pyridazin-2-yl-5-yl; pyridazin-2-yl-6-yl;pyridazin-3-yl-4-yl; pyridazin-3-yl-5-yl; pyridazin-3-yl-6-yl;pyridazin-4-yl-5-yl; pyridazin-4-yl-6-yl; pyridazin-5-yl-6-yl;pyrimidinyl; pyrimidin-1-yl; pyrimidin-2-yl; pyrimidin-3-yl;pyrimidin-4-yl; pyrimidin-5-yl; pyrimidin-6-yl; pyrimidinylyl;pyrimidin-1-yl-2-yl; pyrimidin-1-yl-3-yl; pyrimidin-1-yl-4-yl;pyrimidin-1-yl-5-yl; pyrimidin-1-yl-6-yl; pyrimidin-2-yl-3-yl;pyrimidin-2-yl-4-yl; pyrimidin-2-yl-5-yl; pyrimidin-2-yl-6-yl;pyrimidin-3-yl-4-yl; pyrimidin-3-yl-5-yl; pyrimidin-3-yl-6-yl;pyrimidin-4-yl-5-yl; pyrimidin-4-yl-6-yl; pyrimidin-5-yl-6-yl;pyrazinyl; pyrazin-1-yl; pyrazin-2-yl; pyrazin-3-yl; pyrazin-4-yl;pyrazin-5-yl; pyrazin-6-yl; pyrazinylyl; pyrazin-1-yl-2-yl;pyrazin-1-yl-3-yl; pyrazin-1-yl-4-yl; pyrazin-1-yl-5-yl;pyrazin-1-yl-6-yl; pyrazin-2-yl-3-yl; pyrazin-2-yl-4-yl;pyrazin-2-yl-5-yl; pyrazin-2-yl-6-yl; pyrazin-3-yl-4-yl;pyrazin-3-yl-5-yl; pyrazin-3-yl-6-yl; pyrazin-4-yl-5-yl;pyrazin-4-yl-6-yl; pyrazin-5-yl-6-yl; triazinyl; triazin-1-yl;triazin-2-yl; triazin-3-yl; triazin-4-yl; triazin-5-yl; triazin-6-yl;triazinylyl; triazin-1-yl-2-yl; triazin-1-yl-3-yl; triazin-1-yl-4-yl;triazin-1-yl-5-yl; triazin-1-yl-6-yl; triazin-2-yl-3-yl;triazin-2-yl-4-yl; triazin-2-yl-5-yl; triazin-2-yl-6-yl;triazin-3-yl-4-yl; triazin-3-yl-5-yl; triazin-3-yl-6-yl;triazin-4-yl-5-yl; triazin-4-yl-6-yl; and triazin-5-yl-6-yl. Unlessreference is made to a specific point of attachment, e.g., as inpyrid-2-yl, pyridazin-3-yl, it is intended that such heteroaryl groupscan be bonded to at least one other moiety at any available point ofattachment.

The term “cycloalkyl” refers to a fully saturated and partiallyunsaturated cyclic hydrocarbon group containing from 3 to 8 carbons.Exemplary cycloalkyls include, but are not limited to, for example,cyclopropyl; cyclopropylyl; cycloprop-1-yl-2-yl; cyclobutyl;cyclobutylyl; cyclobut-1-yl-2-yl; cyclobut-1-yl-3-yl; cyclopentyl;cyclopentylyl; cyclopent-1-yl-2-yl; cyclopent-1-yl-3-yl; cyclohexyl;cyclohexylyl; cyclohex-1-yl-2-yl; cyclohex-1-yl-3-yl;cyclohex-1-yl-4-yl; cycloheptyl; cycloheptylyl; cyclohept-1-yl-2-yl;cyclohept-1-yl-3-yl; cyclohept-1-yl-4-yl; cyclooctyl;cyclooct-1-yl-2-yl; cyclooct-1-yl-3-yl; cyclooct-1-yl-4-yl;cyclooct-1-yl-5-yl; cyclobutenyl; cyclobuten-1-yl; cyclobuten-2-yl;cyclobuten-3-yl; cyclobuten-4-yl; cyclobutenylyl; cyclobuten-1-yl-2-yl;cyclobuten-1-yl-3-yl; cyclobuten-1-yl-4-yl; cyclobuten-2-yl-3-yl;cyclobuten-2-yl-4-yl; cyclobuten-3-yl-4-yl; cyclopentenyl;cyclopenten-1-yl; cyclopenten-2-yl; cyclopenten-3-yl; cyclopenten-4-yl;cyclopenten-5-yl; cyclopentenylyl; cyclopenten-1-yl-2-yl;cyclopenten-1-yl-3-yl; cyclopenten-1-yl-4-yl; cyclopenten-1-yl-5-yl;cyclopenten-2-yl-3-yl; cyclopenten-2-yl-4-yl; cyclopenten-2-yl-5-yl;cyclopenten-3-yl-4-yl; cyclopenten-3-yl-5-yl; cyclopenten-4-yl-5-yl;cyclohexenyl; cyclohexen-1-yl; cyclohexen-2-yl; cyclohexen-3-yl;cyclohexen-4-yl; cyclohexen-5-yl; cyclohexen-6-yl; cyclohexenylyl;cyclohexen-1-yl-2-yl; cyclohexen-1-yl-3-yl; cyclohexen-1-yl-4-yl;cyclohexen-1-yl-5-yl; cyclohexen-1-yl-6-yl; cyclohexen-2-yl-3-yl;cyclohexen-2-yl-4-yl; cyclohexen-2-yl-5-yl; cyclohexen-2-yl-6-yl;cyclohexen-3-yl-4-yl; cyclohexen-3-yl-5-yl; cyclohexen-3-yl-6-yl;cyclohexen-4-yl-5-yl; cyclohexen-4-yl-6-yl; and cyclohexen-5-yl-6-yl. Acycloalkyl ring may have a carbon ring atom replaced with a carbonylgroup (C═O). Unless reference is made to a specific point of attachment,e.g. as in cyclohexen-3-yl-6-yl, cycloprop-1-yl-2-yl, andcyclobuten-4-yl, it is intended that such cycloalkyl groups can bebonded to at least one other moiety at any available point ofattachment.

The term “heterocycle” or “heterocyclic” refers to an optionallysubstituted, fully saturated or unsaturated, aromatic or nonaromaticcyclic group, which is, for example, a 4 to 7 membered monocyclic ringsystem containing at least one heteroatom. The heterocycle may contain1, 2 or 3 heteroatoms selected from N, O, and S, where the N and Sheteroatoms may optionally be oxidized and the N heteroatom mayoptionally be quaternized. The heterocycle may be attached via anyheteroatom or carbon atom of the ring.

Exemplary monocyclic heterocycles/heterocyclics include, but are notlimited to, for example, pyrrolidinyl; pyrrolidinylyl; pyrrolyl;pyrrolylyl; indolyl; indolylyl; pyrazolyl; pyrazolylyl; oxetanyl;oxetanylyl; pyrazolinyl; pyrazolinylyl; imidazolyl; imidazolylyl;imidazolinyl; imidazolinylyl; imidazolidinyl; imidazolidinylyl;oxazolyl; oxazolylyl; oxazolidinyl; oxazolidinylyl; isoxazolinyl;isoxazolinylyl; isoxazolyl; isoxazolylyl; thiazolyl; thiazolylyl;thiadiazolyl; thiadiazolylyl; thiazolidinyl; thiazolidinylyl;isothiazolyl; isothiazolylyl; isothiazolidinyl; isothiazolidinylyl;furyl; furylyl; tetrahydrofuryl; tetrahydrofurylyl; thienyl; thienylyl;oxadiazolyl; oxadiazolylyl; piperidinyl; piperidinylyl; piperazinyl;piperazinylyl; 2-oxopiperazinyl; 2-oxopiperazinylyl; 2-oxopiperidinyl;2-oxopiperidinylyl; homopiperazinyl; homopiperazinylyl;2-oxohomopiperazinyl; 2-oxohomopiperazinylyl; 2-oxopyrrolidinyl;2-oxopyrrolidinylyl; 2-oxazepinyl; 2-oxazepinylyl; azepinyl; azepinylyl;4-piperidinyl; 4-piperidinylyl; pyridyl; pyridylyl; N-oxo-pyridyl;N-oxo-pyridylyl; pyrazinyl; pyrazinylyl; pyrimidinyl; pyrimidinylyl;pyridazinyl; pyridazinylyl; tetrahydropyranyl; tetrahydropyranylyl;morpholinyl; morpholinylyl; thiamorpholinyl; thiamorpholinylyl;1,3-dioxolanyl; 1,3-dioxolanylyl; tetrahydro-1,1-dioxothienyl;tetrahydro-1,1-dioxothienylyl; dioxanyl; dioxanylyl; isothiazolidinyl;isothiazolidinylyl; thietanyl; thietanylyl; thiiranyl; thiiranylyl;triazinyl; triazinylyl; triazolyl; and triazolylyl.

The term “heterocycloalkyl” refers to a saturated or unsaturatedcycloalkyl in which at least one ring carbon (and any associatedhydrogen atoms) are independently replaced with at least one heteroatomselected from O and N.

The terms “halogen” and “halo” refer to chlorine, bromine, fluorine, andiodine.

The term “haloalkyl” refers to a C₁-C₃alkyl bonded to a single halogenor multiple halogens. Exemplary haloalkyls containing multiple halogensinclude, but are not limited to, for example, —CHCl₂, —CH₂—CHF₂, and—CF₃.

The term “alkoxy” used alone or as a suffix or prefix, refers toradicals of the general formula —OR^(a), wherein R^(a) is selected froma hydrocarbon radical. Exemplary alkoxys include, but are not limitedto, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy,isobutoxy, cyclopropylmethoxy, allyloxy, and propargyloxy.

The term “cyano” refers to CN.

The phrase “optionally substituted” refers to groups, structures, ormolecules that are substituted with at least one substituent at anyavailable and substitutable position and groups, structures, ormolecules that are not substituted.

The phrase “a compound of formula [insert formula number used inconnection with a specific formula described herein], or enantiomers ordiastereomers thereof, or pharmaceutically acceptable salts of formula[insert formula number used in connection with a specific formuladescribed herein] or enantiomers or diastereomers thereof, or mixturesthereof” refers to the free base of formula [insert formula number usedin connection with a specific formula described herein], enantiomers ofthe free base of formula [insert formula number used in connection witha specific formula described herein], diastereomers of the free base offormula [insert formula number used in connection with a specificformula described herein], pharmaceutically acceptable salts of formula[insert formula number used in connection with a specific formuladescribed herein], pharmaceutically acceptable salts of the enantiomersof formula [insert formula number used in connection with a specificformula described herein], pharmaceutically acceptable salts of thediastereomers of formula [insert formula number used in connection witha specific formula described herein], and/or mixtures of any of theforegoing. The formula number inserted where says “[insert formulanumber used in connection with a specific formula described herein]” isselected from the formula numbers described herein and once selected isinserted into each bracket such that is consistent throughout the phraseand explanation provided therefore. For example, if formula I isselected for insertion into the bracket, the phrase reads “a compound offormula [I], or enantiomers or diastereomers thereof, orpharmaceutically acceptable salts of formula [I] or enantiomers ordiastereomers thereof, or mixtures thereof”, and the explanationprovided therefor reads: “refers to the free base of formula [I],enantiomers of the free base of formula [I], diastereomers of the freebase of formula [I], pharmaceutically acceptable salts of formula [I],pharmaceutically acceptable salts of the enantiomers of formula [I],pharmaceutically acceptable salts of the diastereomers of formula [I],and/or mixtures of any of the foregoing.”

The phrase “a compound of formula [insert formula number used inconnection with a specific formula described herein], or enantiomersthereof, or pharmaceutically acceptable salts of formula [insert formulanumber used in connection with a specific formula described herein] orenantiomers thereof, or mixtures thereof” refers to the free base offormula [insert formula number used in connection with a specificformula described herein], enantiomers of the free base of formula[insert formula number used in connection with a specific formuladescribed herein], pharmaceutically acceptable salts of formula [insertformula number used in connection with a specific formula describedherein], pharmaceutically acceptable salts of the enantiomers of formula[insert formula number used in connection with a specific formuladescribed herein], and/or mixtures of any of the foregoing. The formulanumber inserted where says “[insert formula number used in connectionwith a specific formula described herein]” is selected from the formulanumbers described herein and once selected is inserted into each bracketsuch that is consistent throughout the phrase and explanation providedtherefore. For example, if formula I is selected for insertion into thebracket, the phrase reads “a compound of formula J[I], or enantiomersthereof, or pharmaceutically acceptable salts of formula [I] orenantiomers thereof, or mixtures thereof”, and the explanation providedtherefor reads: “refers to the free base of formula [I], enantiomers ofthe free base of formula [I], pharmaceutically acceptable salts offormula [I], pharmaceutically acceptable salts of the enantiomers offormula [I], and/or mixtures of any of the foregoing.”

In one aspect, the disclosure provides a compound of formula I, orenantiomers or diastereomers thereof, or pharmaceutically acceptablesalts of formula I or enantiomers or diastereomers thereof, or mixturesthereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl; R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰are each independently selected from H and C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—(C₁-C₃alkyl)-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —(C₁-C₃alkyl)-(6-membered heteroaryl containingat least one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹²and the N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy; and

provided:

-   -   i) at least one of R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ is a        C₁-C₃alkyl;    -   ii) formula I is not

-   -    when R¹ is a —C(═O)NR¹¹R¹² group meta-attached to the phenyl,        R² is isopropyl, and R¹¹ and R¹² are H; and    -   iii) formula I is not in the cis configuration at the        cyclopropane.

In another aspect, the disclosure provides a compound of formula Ia, orenantiomers or diastereomers thereof, or pharmaceutically acceptablesalts of formula Ia or enantiomers or diastereomers thereof, or mixturesthereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ are each independently selected fromH and C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—(C₁-C₃alkyl)-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —(C₁-C₃alkyl)-(6-membered heteroaryl containingat least one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹²and the N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy; and

provided:

i) at least one of R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ is a C₁-C₃alkyl;and

ii) formula Ia is not in the cis configuration at the cyclopropane.

In still another aspect, the disclosure provides a compound of formulaIb, or enantiomers or diastereomers thereof, or pharmaceuticallyacceptable salts of formula Ib or enantiomers or diastereomers thereof,or mixtures thereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ are each independently selected fromH and C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—(C₁-C₃alkyl)-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —(C₁-C₃alkyl)-(6-membered heteroaryl containingat least one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹²and the N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy; and

provided:

-   -   i) at least one of R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ is a        C₁-C₃alkyl;    -   ii) formula Ib is not

-   -    when R¹ is —C(═O)NR¹¹R¹², R² is isopropyl, and R¹¹ and R¹² are        H; and    -   iii) formula Ib is not in the cis configuration at the        cyclopropane.

In yet another aspect, the disclosure provides a compound of formula II,or enantiomers or diastereomers thereof, or pharmaceutically acceptablesalts of formula II or enantiomers or diastereomers thereof, or mixturesthereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ are each independently selected fromH and C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—(C₁-C₃alkyl)-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —(C₁-C₃alkyl)-(6-membered heteroaryl containingat least one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹²and the N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy; and

provided:

-   -   i) at least one of R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ is a        C₁-C₃alkyl; and    -   ii) formula II is not

-   -    when R¹ is —C(═O)NR¹¹R¹², R² is isopropyl, and R¹¹ and R¹² are        H.

In another aspect, the disclosure provides a compound of formula IIa, orenantiomers or diastereomers thereof, or pharmaceutically acceptablesalts of formula IIa or enantiomers or diastereomers thereof, ormixtures thereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ are each independently selected fromH and C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—(C₁-C₃alkyl)-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —(C₁-C₃alkyl)-(6-membered heteroaryl containingat least one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹²and the N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy; and

provided:

i) at least one of R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ is a C₁-C₃alkyl.

In yet still another aspect, the disclosure provides a compound offormula IIb, or enantiomers or diastereomers thereof, orpharmaceutically acceptable salts of formula IIb or enantiomers ordiastereomers thereof, or mixtures thereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ are each independently selected fromH and C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—(C₁-C₃alkyl)-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —(C₁-C₃alkyl)-(6-membered heteroaryl containingat least one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹²and the N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy; and

provided:

-   -   i) at least one of R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ is a        C₁-C₃alkyl; and    -   ii) formula IIb is not

-   -    when R¹ is —C(═O)NR¹¹R¹², R² is isopropyl, and R¹¹ and R¹² are        H.

In even yet another aspect, the disclosure provides a compound offormula III, or enantiomers or diastereomers thereof, orpharmaceutically acceptable salts of formula III or enantiomers ordiastereomers thereof, or mixtures thereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ are each independently selected fromH and C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—(C₁-C₃alkyl)-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —(C₁-C₃alkyl)-(6-membered heteroaryl containingat least one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹²and the N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy; and

provided:

-   -   i) at least one of R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ is a        C₁-C₃alkyl; and    -   ii) formula III is not

-   -    when R¹ is a —C(═O)NR¹¹R¹², R² is isopropyl, and R¹¹ and R¹²        are H.

In still yet another aspect, the disclosure provides a compound offormula IIIa, or enantiomers or diastereomers thereof, orpharmaceutically acceptable salts of formula IIIa or enantiomers ordiastereomers thereof, or mixtures thereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ are each independently selected fromH and C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—(C₁-C₃alkyl)-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —(C₁-C₃alkyl)-(6-membered heteroaryl containingat least one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹²and the N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy; and

provided:

i) at least one of R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ is a C₁-C₃alkyl.

In even still yet another aspect, the disclosure provides a compound offormula IIIb, or enantiomers or diastereomers thereof, orpharmaceutically acceptable salts of formula IIIb or enantiomers ordiastereomers thereof, or mixtures thereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ are each independently selected fromH and C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—(C₁-C₃alkyl)-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —(C₁-C₃alkyl)-(6-membered heteroaryl containingat least one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹²and the N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy; and

provided:

-   -   i) at least one of R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ is a        C₁-C₃alkyl; and    -   ii) formula IIIb is not

-   -    when R¹ is —C(═O)NR¹¹R¹², R² is isopropyl, and R¹¹ and R¹² are        H.

In yet another aspect, the disclosure provides a compound of formula IV,or enantiomers or diastereomers thereof, or pharmaceutically acceptablesalts of formula IV or enantiomers or diastereomers thereof, or mixturesthereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R⁵ is C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—C₁-C₃alkyl-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —C₁-C₃alkyl-(6-membered heteroaryl containing atleast one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹² andthe N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy; and

provided:

i) formula IV is not in the cis configuration at the cyclopropane.

In still yet another aspect, the disclosure provides a compound offormula IVa, or enantiomers or diastereomers thereof, orpharmaceutically acceptable salts of formula IVa or enantiomers ordiastereomers thereof, or mixtures thereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R⁵ is C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—C₁-C₃alkyl-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —C₁-C₃alkyl-(6-membered heteroaryl containing atleast one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹² andthe N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy; and

provided:

i) formula IVa is not in the cis configuration at the cyclopropane.

In even still yet another aspect, the disclosure provides a compound offormula IVb, or enantiomers or diastereomers thereof, orpharmaceutically acceptable salts of formula IVb or enantiomers ordiastereomers thereof, or mixtures thereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R⁵ is C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—C₁-C₃alkyl-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —C₁-C₃alkyl-(6-membered heteroaryl containing atleast one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹² andthe N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy; and provided:

i) formula IVb is not in the cis configuration at the cyclopropane.

In a further aspect, the disclosure provides a compound of formula V, orpharmaceutically acceptable salts thereof, or mixtures thereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R⁵ is C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—C₁-C₃alkyl-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —C₁-C₃alkyl-(6-membered heteroaryl containing atleast one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹² andthe N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy.

In a still further aspect, the disclosure provides a compound of formulaVa, or pharmaceutically acceptable salts thereof, or mixtures thereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R⁵ is C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—C₁-C₃alkyl-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —C₁-C₃alkyl-(6-membered heteroaryl containing atleast one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹² andthe N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy.

In yet a further aspect, the disclosure provides a compound of formulaVb, or pharmaceutically acceptable salts thereof, or mixtures thereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R⁵ is C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—C₁-C₃alkyl-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —C₁-C₃alkyl-(6-membered heteroaryl containing atleast one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹² andthe N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy.

In an even further aspect, the disclosure provides a compound of formulaVI, or enantiomers or diastereomers thereof, or pharmaceuticallyacceptable salts of formula VI or enantiomers or diastereomers thereof,or mixtures thereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R⁴ is C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—C₁-C₃alkyl-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —C₁-C₃alkyl-(6-membered heteroaryl containing atleast one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹² andthe N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy; and

provided:

i) formula VI is not in the cis configuration at the cyclopropane.

In a still even further aspect, the disclosure provides a compound offormula VIa, or enantiomers or diastereomers thereof, orpharmaceutically acceptable salts of formula VIa or enantiomers ordiastereomers thereof, or mixtures thereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R⁴ is C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—C₁-C₃alkyl-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —C₁-C₃alkyl-(6-membered heteroaryl containing atleast one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹² andthe N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy; and provided:

i) formula VIa is not in the cis configuration at the cyclopropane.

In yet a still even further aspect, the disclosure provides a compoundof formula VIb, or enantiomers or diastereomers thereof, orpharmaceutically acceptable salts of formula VIb or enantiomers ordiastereomers thereof, or mixtures thereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R⁴ is C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—C₁-C₃alkyl-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —C₁-C₃alkyl-(6-membered heteroaryl containing atleast one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹² andthe N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy; and

provided:

i) formula VIb is not in the cis configuration at the cyclopropane.

In another aspect, the disclosure provides a compound of formula VII, orpharmaceutically acceptable salts thereof, or mixtures thereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R⁴ is C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—C₁-C₃alkyl-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —C₁-C₃alkyl-(6-membered heteroaryl containing atleast one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹² andthe N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy.

In still another aspect, the disclosure provides a compound of formulaVIIa, or pharmaceutically acceptable salts thereof, or mixtures thereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R⁴ is C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—C₁-C₃alkyl-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —C₁-C₃alkyl-(6-membered heteroaryl containing atleast one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹² andthe N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy.

In yet still another aspect, the disclosure provides a compound offormula VIIb, or pharmaceutically acceptable salts thereof, or mixturesthereof:

-   -   VIIb        wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R⁴ is C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—C₁-C₃alkyl-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —C₁-C₃alkyl-(6-membered heteroaryl containing atleast one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹² andthe N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy.

In yet another aspect, the disclosure provides a compound of formulaVIII, or pharmaceutically acceptable salts thereof, or mixtures thereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R⁵ is C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—C₁-C₃alkyl-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —C₁-C₃alkyl-(6-membered heteroaryl containing atleast one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹² andthe N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy.

In yet still an even further aspect, the disclosure provides a compoundof formula VIIIa or pharmaceutically acceptable salts thereof, ormixtures thereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R⁵ is C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—C₁-C₃alkyl-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —C₁-C₃alkyl-(6-membered heteroaryl containing atleast one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹² andthe N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy.

In even still another aspect, the disclosure provides a compound offormula VIIIb or pharmaceutically acceptable salts thereof, or mixturesthereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R⁵ is C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—C₁-C₃alkyl-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —C₁-C₃alkyl-(6-membered heteroaryl containing atleast one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹² andthe N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy.

In an even still further aspect, the disclosure provides a compound offormula IX, or pharmaceutically acceptable salts thereof, or mixturesthereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R⁴ is C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—C₁-C₃alkyl-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —C₁-C₃alkyl-(6-membered heteroaryl containing atleast one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹² andthe N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy.

In still another aspect, the disclosure provides a compound of formulaIXa, or pharmaceutically acceptable salts thereof, or mixtures thereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R⁴ is C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—C₁-C₃alkyl-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —C₁-C₃alkyl-(6-membered heteroaryl containing atleast one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹² andthe N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy.

In a still further aspect, the disclosure provides a compound of formulaIXb, or pharmaceutically acceptable salts thereof, or mixtures thereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R⁴ is C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—C₁-C₃alkyl-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —C₁-C₃alkyl-(6-membered heteroaryl containing atleast one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹² andthe N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy.

In yet another aspect, the disclosure provides a compound of formula X,or enantiomers or diastereomers thereof, or pharmaceutically acceptablesalts of formula X or enantiomers or diastereomers thereof, or mixturesthereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R⁵ is C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—C₁-C₃alkyl-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —C₁-C₃alkyl-(6-membered heteroaryl containing atleast one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹² andthe N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy; and

provided:

i) formula X is not in the cis configuration at the cyclopropane.

In still yet another aspect, the disclosure provides a compound offormula Xa, or enantiomers or diastereomers thereof, or pharmaceuticallyacceptable salts of formula Xa or enantiomers or diastereomers thereof,or mixtures thereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R⁵ is C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—C₁-C₃alkyl-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —C₁-C₃alkyl-(6-membered heteroaryl containing atleast one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹² andthe N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy; and

provided:

i) formula Xa is not in the cis configuration at the cyclopropane.

In even still yet another aspect, the disclosure provides a compound offormula Xb, or enantiomers or diastereomers thereof, or pharmaceuticallyacceptable salts of formula Xb or enantiomers or diastereomers thereof,or mixtures thereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R⁵ is C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—C₁-C₃alkyl-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —C₁-C₃alkyl-(6-membered heteroaryl containing atleast one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹² andthe N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy; and provided:

i) formula Xb is not in the cis configuration at the cyclopropane.

In a further aspect, the disclosure provides a compound of formula XI,or pharmaceutically acceptable salts thereof, or mixtures thereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R⁵ is C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—C₁-C₃alkyl-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —C₁-C₃alkyl-(6-membered heteroaryl containing atleast one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹² andthe N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy.

In a still further aspect, the disclosure provides a compound of formulaXIa, or pharmaceutically acceptable salts thereof, or mixtures thereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R⁵ is C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—C₁-C₃alkyl-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —C₁-C₃alkyl-(6-membered heteroaryl containing atleast one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹² andthe N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy.

In yet a further aspect, the disclosure provides a compound of formulaXIb, or pharmaceutically acceptable salts thereof, or mixtures thereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R⁵ is C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—C₁-C₃alkyl-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —C₁-C₃alkyl-(6-membered heteroaryl containing atleast one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹² andthe N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy.

In an even further aspect, the disclosure provides a compound of formulaXII, or enantiomers or diastereomers thereof, or pharmaceuticallyacceptable salts of formula XII or enantiomers or diastereomers thereof,or mixtures thereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R⁴ is C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—C₁-C₃alkyl-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —C₁-C₃alkyl-(6-membered heteroaryl containing atleast one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹² andthe N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy; and

provided:

i) formula XII is not in the cis configuration at the cyclopropane.

In a still even further aspect, the disclosure provides a compound offormula XIIa, or enantiomers or diastereomers thereof, orpharmaceutically acceptable salts of formula XIIa or enantiomers ordiastereomers thereof, or mixtures thereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R⁴ is C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—C₁-C₃alkyl-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —C₁-C₃alkyl-(6-membered heteroaryl containing atleast one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹² andthe N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy; and

provided:

i) formula XIIa is not in the cis configuration at the cyclopropane.

In yet a still even further aspect, the disclosure provides a compoundof formula XIIb, or enantiomers or diastereomers thereof, orpharmaceutically acceptable salts of formula XIIb or enantiomers ordiastereomers thereof, or mixtures thereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R⁴ is C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—C₁-C₃alkyl-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —C₁-C₃alkyl-(6-membered heteroaryl containing atleast one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹² andthe N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy; and

provided:

i) formula XIIb is not in the cis configuration at the cyclopropane.

In another aspect, the disclosure provides a compound of formula XIII,or pharmaceutically acceptable salts thereof, or mixtures thereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R⁴ is C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—C₁-C₃alkyl-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —C₁-C₃alkyl-(6-membered heteroaryl containing atleast one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹² andthe N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy.

In still another aspect, the disclosure provides a compound of formulaXIIIa, or pharmaceutically acceptable salts thereof, or mixturesthereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R⁴ is C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—C₁-C₃alkyl-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —C₁-C₃alkyl-(6-membered heteroaryl containing atleast one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹² andthe N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy.

In yet still another aspect, the disclosure provides a compound offormula XIIIb, or pharmaceutically acceptable salts thereof, or mixturesthereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R⁴ is C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—C₁-C₃alkyl-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —C₁-C₃alkyl-(6-membered heteroaryl containing atleast one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹² andthe N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy.

In yet another aspect, the disclosure provides a compound of formulaXIV, or pharmaceutically acceptable salts thereof, or mixtures thereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R⁵ is C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—C₁-C₃alkyl-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —C₁-C₃alkyl-(6-membered heteroaryl containing atleast one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹² andthe N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy.

In yet still an even further aspect, the disclosure provides a compoundof formula XIVa or pharmaceutically acceptable salts thereof, ormixtures thereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R⁵ is C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—C₁-C₃alkyl-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —C₁-C₃alkyl-(6-membered heteroaryl containing atleast one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹² andthe N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy.

In even still another aspect, the disclosure provides a compound offormula XIVb or pharmaceutically acceptable salts thereof, or mixturesthereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R⁵ is C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—C₁-C₃alkyl-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —C₁-C₃alkyl-(6-membered heteroaryl containing atleast one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹² andthe N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy.

In an even still further aspect, the disclosure provides a compound offormula XV, or pharmaceutically acceptable salts thereof, or mixturesthereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R⁴ is C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—C₁-C₃alkyl-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —C₁-C₃alkyl-(6-membered heteroaryl containing atleast one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹² andthe N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy.

In still another aspect, the disclosure provides a compound of formulaXVa, or pharmaceutically acceptable salts thereof, or mixtures thereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R⁴ is C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—C₁-C₃alkyl-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —C₁-C₃alkyl-(6-membered heteroaryl containing atleast one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹² andthe N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy.

In a still further aspect, the disclosure provides a compound of formulaXVb, or pharmaceutically acceptable salts thereof, or mixtures thereof:

wherein:

R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy, —C₁-C₆alkyl-hydroxy,—C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², heterocycle, cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen;

R² is C₁-C₆alkyl or C₃-C₆cycloalkyl;

R⁴ is C₁-C₃alkyl; and

R¹¹ and R¹² are each independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—C₁-C₃alkyl-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —C₁-C₃alkyl-(6-membered heteroaryl containing atleast one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹² andthe N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy.

In another embodiment, R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy,—C₁-C₆alkyl-hydroxy, —C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹², cyano,haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen.

In still yet another embodiment, R¹ is —C(═O)NR¹¹R¹².

In yet another embodiment, R² is C₁-C₆alkyl.

In still another embodiment, R² is C₃-C₆cycloalkyl.

In a further embodiment, R² is C₁-C₃alkyl.

In yet another embodiment, R² is isopropyl or cyclobutyl.

In an even further embodiment, R³ is H or methyl.

In still yet a further embodiment, R³ is H.

In even a further embodiment, R³ is methyl.

In yet a further embodiment, R⁴ is H or methyl.

In yet an even further embodiment, R⁴ is H.

In still yet an even further embodiment, R⁴ is methyl.

In a still yet a further embodiment, R⁵ is H, methyl, or ethyl.

In even a further embodiment, R⁵ is H.

In still an even further embodiment, R⁵ is methyl.

In still yet a further embodiment, R⁵ is ethyl.

In still yet another embodiment, R⁶ is H or methyl.

In still yet an even further embodiment, R⁶ is H.

In still another embodiment, R⁶ is methyl.

In yet another embodiment, R⁷, R⁸, R⁹, and R¹⁰ are each independently H.

Yet an even further embodiment is directed to at least one compoundselected from:4-(trans-2-((R)-4-isopropyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,diastereomeric mixture;4-(trans-2-((R)-4-isopropyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 1;4-(trans-2-((R)-4-isopropyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 2;4-(trans-2-((S)-4-isopropyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,diastereomeric mixture;4-(trans-2-((S)-4-isopropyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 1;4-(trans-2-((S)-4-isopropyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 2;4-(trans-2-((R)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,diastereomeric mixture;4-(trans-2-((R)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 1;4-(trans-2-((R)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 2;4-(trans-2-((S)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,diastereomeric mixture;4-(trans-2-((S)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 1;4-(trans-2-((S)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 2;4-(trans-2-((R)-4-cyclobutyl-2-ethylpiperazine-1-carbonyl)cyclopropyl)benzamide,diastereomeric mixture;4-(trans-2-((R)-4-cyclobutyl-2-ethylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 1;4-(trans-2-((R)-4-cyclobutyl-2-ethylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 2;4-(trans-2-((S)-4-cyclobutyl-2-ethylpiperazine-1-carbonyl)cyclopropyl)benzamide,diastereomeric mixture;4-(trans-2-((S)-4-cyclobutyl-3-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,diastereomeric mixture;4-(trans-2-((S)-4-cyclobutyl-3-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 1;4-(trans-2-((S)-4-cyclobutyl-3-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 2;4-(trans-2-((R)-4-cyclobutyl-3-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,diastereomeric mixture;4-(trans-2-((R)-4-cyclobutyl-3-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 1;4-(trans-2-((R)-4-cyclobutyl-3-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 2;4-(trans-2-(4-cyclobutyl-2,2-dimethylpiperazine-1-carbonyl)cyclopropyl)benzamide,enantiomeric mixture;4-(trans-2-(4-cyclobutyl-3,3-dimethylpiperazine-1-carbonyl)cyclopropyl)benzamide,enantiomeric mixture;4-(trans-2-(4-cyclobutyl-3,3-dimethylpiperazine-1-carbonyl)cyclopropyl)benzamide,enantiomer 1;4-(trans-2-(4-cyclobutyl-3,3-dimethylpiperazine-1-carbonyl)cyclopropyl)benzamide,enantiomer 2;3-(trans-2-((R)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,diastereomeric mixture;3-(trans-2-((R)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 1;3-(trans-2-((R)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 2;3-(trans-2-((S)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,diastereomeric mixture;3-(trans-2-((S)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 1;3-(trans-2-((S)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 2;3-(trans-2-((S)-4-cyclobutyl-3-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,diastereomeric mixture;4-{(1S,2S)-2-[((R)-4-Cyclobutyl-2-methylpiperazin-1-yl)carbonyl]-cyclopropyl}-benzamide;and3-(trans-2-((R)-4-cyclobutyl-3-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,diastereomeric mixture; and pharmaceutically acceptable salts thereof ormixtures thereof.

Another embodiment is directed to at least one compound selected from:4-(trans-2-((R)-4-isopropyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 1;4-(trans-2-((S)-4-isopropyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 1;4-((trans)-2-((R)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 1;4-((trans)-2-((S)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 1;4-(trans-2-((R)-4-cyclobutyl-2-ethylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 1;4-((trans)-2-((S)-4-cyclobutyl-3-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 1;4-((trans)-2-((R)-4-cyclobutyl-3-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 1;4-(trans-2-(4-cyclobutyl-3,3-dimethylpiperazine-1-carbonyl)cyclopropyl)benzamide,enantiomer 1;3-((trans)-2-((R)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 1;4-{(1S,2S)-2-[((R)-4-Cyclobutyl-2-methylpiperazin-1-yl)carbonyl]-cyclopropyl}-benzamide;and3-((trans)-2-((S)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 1; and pharmaceutically acceptable salts thereof or mixturesthereof.

If compounds of the present invention contain one or more chiralcenters, the compounds of the invention may exist 1) in (and be isolatedas) enantiomeric or diastereomeric forms, and/or 2) as a racemicmixture. The present invention includes any possible enantiomers,diastereomers, racemates or mixtures thereof, of the compounds of theformulae described herein. The optically active forms of the compound ofthe invention may be prepared, for example, by chiral chromatographicseparation of a racemate, by synthesis from optically active startingmaterials or by asymmetric synthesis based on the procedures describedhereafter.

It will also be understood that certain compounds of the invention mayexist in solvated, for example hydrated, as well as unsolvated forms. Itwill further be understood that the present invention encompasses allsuch solvated forms of the compounds of the formulae described hereinthat possess the activity mentioned hereinbelow.

The compounds of the formulae described herein can also form salts. As aresult, when a compound of a formulae described herein is referred to,such reference includes, unless otherwise indicated, salts thereof. Inone embodiment, the compounds of the formulae described herein formpharmaceutically acceptable salts. In another embodiment, the compoundsof the formulae described herein form salts that can, for example, beused to isolate and/or purify the compounds of the formulae describedherein.

Generally, pharmaceutically acceptable salts of a compound in accordancewith the formulae described herein can be obtained by using standardprocedures well known in the art. These standard procedures include, butare not limited to, for example, the reacting of a sufficiently basiccompound, such as, for example, an alkyl amine with a suitable acid,such as, for example, HCl or acetic acid, to afford a physiologicallyacceptable anion. It may also be possible to make a corresponding alkalimetal (such as sodium, potassium, or lithium) or an alkaline earth metal(such as a calcium) salt by treating a compound in accordance with theformulae described herein, which have a suitably acidic proton, such as,for example, a carboxylic acid or a phenol with one equivalent of analkali metal or alkaline earth metal hydroxide or alkoxide (such as, forexample, an ethoxide or methoxide), or a suitably basic organic amine(such as, for example, a choline or meglumine) in an aqueous medium,followed by conventional purification techniques.

In one embodiment, a compound in accordance with the formulae describedherein may be converted to a pharmaceutically acceptable salt or solvatethereof, particularly, an acid addition salt, such as, for example,hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate,tartrate, citrate, methanesulphonate, and p-toluenesulphonate.

In general, the compounds of the formulae described herein can beprepared in accordance with the following Schemes and the generalknowledge of one skilled in the art and/or in accordance with themethods set forth in the Examples that follow. Solvents, temperatures,pressures, and other reaction conditions may readily be selected by oneof ordinary skill in the art. Starting materials are commerciallyavailable or readily prepared by one skilled in the art. Combinatorialtechniques can be employed in the preparation of compounds, for example,where the intermediates possess groups suitable for these techniques.

The term “amino-protecting group” refers to art-recognized moietiescapable of attaching to an amino group so as to prevent the amino groupfrom taking place in reactions occurring elsewhere on the molecule towhich the amino group is attached. Acceptable amino-protecting groups,include but are not limited to, for example, amino-protecting groupsdescribed in “Protective Groups in Organic Synthesis”, 2nd edition, JohnWiley & Sons, 1981. The amino-protecting group may be, for example, aurethane type protective group (which is also referred to as a carbamateprotective group), which includes but is not limited to, for example,arylalkyloxycarbonyl groups, such as, for example, benzyloxycarbonyl;and alkoxycarbonyl groups, such as, for example, methoxycarbonyl andtert-butoxycarbonyl. Typically, the amino-protecting group istert-butoxycarbonyl.

Another aspect of the disclosure is directed to a method for treating adisorder in which modulating the histamine H3 receptor is beneficialcomprising administering to a warm-blooded animal in need of suchtreatment a therapeutically effective amount of at least one compoundaccording to at least one formula described herein, or diastereomers orenantiomers thereof, or pharmaceutically acceptable salts of saidformula, or diastereomers or enantiomers thereof, or mixtures thereof.

At least one compound in accordance with at least one formula describedherein may be used to treat a wide range of conditions or disorders inwhich interacting with the histamine H3 receptor is beneficial. At leastone compound in accordance with at least one formula describe hereinmay, for example, be useful to treat diseases of the central nervoussystem, the peripheral nervous system, the cardiovascular system, thepulmonary system, the gastrointestinal system, or the endocrinologicalsystem.

In one embodiment, at least one compound in accordance with at least oneformula described herein modulates at least one histamine H3 receptor.

The terms “modulate”, “modulates”, “modulating”, or “modulation”, asused herein, refer to, for example, the activation (e.g., agonistactivity) or inhibition (e.g., antagonist and inverse agonist activity)of at least one histamine H3 receptor.

In one embodiment, at least one compound in accordance with at least oneformula described herein is an inverse agonist of at least one histamineH3 receptor.

In another embodiment, at least one compound in accordance with at leastone formula described herein is an antagonist of at least one histamineH3 receptor.

In another embodiment, at least one compound in accordance with at leastone formula described herein is an antagonist of at least one histamineH3 receptor.

In yet another embodiment, at least one compound in accordance with atleast one formula described herein is an antagonist of at least onehistamine H3 receptor.

Another embodiment provides a method for treating a disorder in whichmodulating the function of at least one histamine H3 receptor isbeneficial comprising administering to a warm-blooded animal in need ofsuch treatment a therapeutically effective amount of at least onecompound according to at least one formula described herein.

In yet another embodiment, at least one compound in accordance with atleast one formula described herein may be used as a medicament.

At least one compound in accordance with at least one formula describedherein may be useful to treat at least one autoimmune disorder.Exemplary autoimmune disorders include, but are not limited to, forexample, arthritis, skin grafts, organ transplants and similar surgicalneeds, collagen diseases, various allergies, tumors and viruses.

At least one compound in accordance with at least one formula describedherein may be useful to treat at least one psychiatric disorder.Exemplary psychiatric disorders include, but are not limited to, forexample, Psychotic Disorder(s) and Schizophrenia Disorder(s), such as,for example, Schizoaffective Disorder(s), Delusional Disorder(s), BriefPsychotic Disorder(s), Shared Psychotic Disorder(s), and PsychoticDisorder(s) Due to a General Medical Condition; Dementia and otherCognitive Disorder(s); Anxiety Disorder(s), such as, for example, PanicDisorder(s) Without Agoraphobia, Panic Disorder(s) With Agoraphobia,Agoraphobia Without History of Panic Disorder(s), Specific Phobia,Social Phobia, Obsessive-Compulsive Disorder(s), Stress relatedDisorder(s), Posttraumatic Stress Disorder(s), Acute Stress Disorder(s),Generalized Anxiety Disorder(s) and Generalized Anxiety Disorder(s) Dueto a General Medical Condition; Mood Disorder(s), such as, for example,a) Depressive Disorder(s) (including but not limited to, for example,Major Depressive Disorder(s) and Dysthymic Disorder(s)), b) BipolarDepression and/or Bipolar mania, such as, for example, Bipolar I (whichincludes, but is not limited to those with manic, depressive or mixedepisodes), and Bipolar II, c) Cyclothymiac's Disorder(s), and d) MoodDisorder(s) Due to a General Medical Condition; Sleep Disorder(s), suchas, for example, narcolepsy; Disorder(s) Usually First Diagnosed inInfancy, Childhood, or Adolescence including, but not limited to, forexample, Mental Retardation, Downs Syndrome, Learning Disorder(s), MotorSkills Disorder(s), Communication Disorders(s), Pervasive DevelopmentalDisorder(s), Attention-Deficit and Disruptive Behavior Disorder(s),Feeding and Eating Disorder(s) of Infancy or Early Childhood, TicDisorder(s), and Elimination Disorder(s); Substance-Related Disorder(s)including, but not limited to, for example, Substance Dependence,Substance Abuse, Substance Intoxication, Substance Withdrawal,Alcohol-Related Disorder(s), Amphetamines (or Amphetamine-Like)-RelatedDisorder(s), Caffeine-Related Disorder(s), Cannabis-Related Disorder(s),Cocaine-Related Disorder(s), Hallucinogen-Related Disorder(s),Inhalant-Related Disorder(s), Nicotine-Related Disorder(s)s,Opiod-Related Disorder(s)s, Phencyclidine (orPhencyclidine-Like)-Related Disorder(s), and Sedative-, Hypnotic- orAnxiolytic-Related Disorder(s); Attention-Deficit and DisruptiveBehavior Disorder(s); Eating Disorder(s), such as, for example, obesity;Personality Disorder(s) including, but not limited to, for example,Obsessive-Compulsive Personality Disorder(s); Impulse-ControlDisorder(s); Tic Disorders including, but not limited to, for exampleTourette's Disorder, Chronic motor or vocal tic disorder; and TransientTic Disorder.

At least one of the above psychiatric disorders is defined, for example,in the American Psychiatric Association: Diagnostic and StatisticalManual of Mental Disorders, Fourth Edition, Text Revision, Washington,D.C., American Psychiatric Association, 2000.

At least one compound in accordance with at least one formula describedherein may be useful i) to treat obesity or being overweight (e.g.,promotion of weight loss and maintenance of weight loss), eatingdisorders (e.g., binge eating, anorexia, bulimia and compulsive), and/orcravings (for drugs, tobacco, alcohol, any appetizing macronutrients ornon-essential food items); ii) to prevent weight gain (e.g.,medication-induced or subsequent to cessation of smoking); and/or iii)to modulate appetite and/or satiety.

At least one compound in accordance with at least one formula describedherein may be suitable for treating obesity by reducing appetite andbody weight and/or maintaining weight reduction and preventing rebound.

At least one compound in accordance with at least one formula describedherein may be used to prevent or reverse medication-induced weight gain,e.g. weight gain caused by antipsychotic (neuroleptic) treatment(s);and/or weight gain associated with smoking cessation.

At least one compound in accordance with at least one formula describedherein may be useful to treat at least one Neurodegenerative Disorder.Exemplary Neurodegenerative Disorders include, but are not limited to,for example, Alzheimer's Disease (AD); Dementia, which includes, but isnot limited to, for example, Alzheimer's Disease (AD), Down syndrome,vascular dementia, Parkinson's Disease (PD), postencephelaticparkinsonism, dementia with Lewy bodies, HIV dementia, Huntington'sDisease, amyotrophic lateral sclerosis (ALS), motor neuron diseases(MND), Frontotemporal dementia Parkinson's Type (FTDP), progressivesupranuclear palsy (PSP), Pick's Disease, Niemann-Pick's Disease,corticobasal degeneration, traumatic brain injury (TBI), dementiapugilistica, Creutzfeld-Jacob Disease and prion diseases; CognitiveDeficit in Schizophrenia (CDS); Mild Cognitive Impairment (MCI);Age-Associated Memory Impairment (AAMI); Age-Related Cognitive Decline(ARCD); Cognitive Impairement No Dementia (CIND); Multiple Sclerosis;Parkinson's Disease (PD); postencephalitic parkinsonism; Huntington'sDisease; amyotrophic lateral sclerosis (ALS); motor neuron diseases(MND); Multiple System Atrophy (MSA); Corticobasal Degeneration;Progressive Supranuclear Paresis; Guillain-Barré Syndrome (GBS); andChronic Inflammatory Demyelinating Polyneuropathy (CIDP).

At least one compound in accordance with the formulae described hereinmay be useful to treat at least one Neuroinflammatory Disorderincluding, but not limited to, for example, Multiple Sclerosis (MS),which includes, but is not limited to, for example, Relapse RemittingMultiple Sclerosis (RRMS), Secondary Progressive Multiple Sclerosis(SPMS), and Primary Progressive Multiple Sclerosis (PPMS); Parkinson'sdisease; Multiple System Atrophy (MSA); Corticobasal Degeneration;Progressive Supranuclear Paresis; Guillain-Barré Syndrome (GBS); andchronic inflammatory demyelinating polyneuropathy (CIDP).

At least one compound in accordance with at least one formula describedherein may be useful to treat at least one Attention-Deficit andDisruptive Behavior Disorder. Exemplary Attention-Deficit and DisruptiveBehavior Disorders include, but are not limited to, for example,attention deficit disorder (ADD), attention deficit hyperactivitydisorder (ADHD), and affective disorders.

At least one compound in accordance with at least one formula describedherein may be useful to treat pain; acute and chronic pain disordersincluding but not limited to, for example, Widespread pain, Localizedpain, Nociceptive pain, Inflammatory pain, Central pain, Central andperipheral neuropathic pain, Central and peripheral neurogenic pain,Central and peripheral neuralgia, Low back pain, Postoperative pain,Visceral pain, and Pelvic pain; Allodynia; Anesthesia dolorosa;Causalgia; Dysesthesia; Fibromyalgia; Hyperalgesia; Hyperesthesia;Hyperpathia; Ischemic pain; Sciatic pain; Pain associated with cystitisincluding, but not limited to, interstitial cystitis; Pain associatedwith multiple sclerosis; Pain associated with arthritis; Pain associatedwith osteoarthritis; Pain associated with rheumatoid arthritis; and Painassociated with cancer.

At least one compound in accordance with at least one formula describedherein may be used for the manufacture of a medicament for the treatmentof at least one autoimmune disorder, psychiatric disorder, obesitydisorder, eating disorder, craving disorder, neurodegenerative disorder,neuroinflammatory disorder, Attention-Deficit and Disruptive BehaviourDisorder, and/or pain disorder described hereinabove.

For example, in one embodiment at least one compound in accordance withat least one formula described herein may be used for the manufacture ofa medicament for the treatment of at least one autoimmune disorder,psychiatric disorder, obesity disorder, eating disorder, cravingdisorder, neurodegenerative disorder, neuroinflammatory disorder,Attention-Deficit and Disruptive Behaviour Disorder, and/or paindisorder described hereinabove.

At least one compound in accordance with at least one formula describedherein may be used for the manufacture of a medicament for the treatmentof at least one disorder selected from cognitive deficit inschizophrenia, narcolepsy, attention deficit hyperactivity disorder,obesity, pain, and Alzheimer's disease.

For example, in one embodiment at least one compound in accordance withformula I may be used for the manufacture of a medicament for thetreatment of at least one disorder selected from cognitive deficit inschizophrenia, narcolepsy, attention deficit hyperactivity disorder,obesity, pain, and Alzheimer's disease.

At least one compound in accordance with at least one formula describedherein may be used for the treatment of at least one disorder selectedfrom cognitive deficit in schizophrenia, narcolepsy, obesity, attentiondeficit hyperactivity disorder, pain, and Alzheimer's disease.

For example, one embodiment provides at least one compound in accordancewith formula I for the treatment of at least one disorder selected fromcognitive deficit in schizophrenia, narcolepsy, obesity, attentiondeficit hyperactivity disorder, pain, and Alzheimer's disease.

At least one compound in accordance with at least one formula describedherein may be used for the treatment of at least one disorder selectedfrom cognitive deficit in schizophrenia and Alzheimer's disease.

For example, one embodiment provides at least one compound in accordancewith formula I for the treatment of at least one disorder selected fromcognitive deficit in schizophrenia and Alzheimer's disease.

Another aspect provides a method for treating at least one autoimmunedisorder, psychiatric disorder, obesity disorder, eating disorder,craving disorder, neurodegenerative disorder, neuroinflammatorydisorder, attention-deficit and disruptive behaviour disorder, and/orpain disorder in a warm-blooded animal, comprising administering to saidanimal in need of such treatment a therapeutically effective amount ofat least one compound in accordance with at least one formula describedherein.

For example, one embodiment provides a method for treating at least oneautoimmune disorder, psychiatric disorder, obesity disorder, eatingdisorder, craving disorder, neurodegenerative disorder,neuroinflammatory disorder, attention-deficit and disruptive behaviourdisorder, and/or pain disorder in a warm-blooded animal, comprisingadministering to said animal in need of such treatment a therapeuticallyeffective amount of at least one compound according to formula I.

Yet another aspect provides a method for treating at least one disorderselected from cognitive deficit in schizophrenia, narcolepsy, obesity,attention deficit hyperactivity disorder, pain, and Alzheimer's diseasein a warm-blooded animal, comprising administering to said animal inneed of such treatment a therapeutically effective amount of at leastone compound in accordance with at least one formula described herein.

For example, one embodiment provides a method for treating at least onedisorder selected from cognitive deficit in schizophrenia, narcolepsy,obesity, attention deficit hyperactivity disorder, pain, and Alzheimer'sdisease in a warm-blooded animal, comprising administering to saidanimal in need of such treatment a therapeutically effective amount ofat least one compound according to formula I.

Yet another aspect provides a method for treating cognitive deficit inschizophrenia in a warm-blooded animal, comprising administering to saidanimal in need of such treatment a therapeutically effective amount ofat least one compound in accordance with at least one formula describedherein.

For example, one embodiment provides a method for treating cognitivedeficit in schizophrenia in a warm-blooded animal, comprisingadministering to said animal in need of such treatment a therapeuticallyeffective amount of at least one compound according to formula I.

Yet another aspect provides a method for treating obesity in awarm-blooded animal, comprising administering to said animal in need ofsuch treatment a therapeutically effective amount of at least onecompound in accordance with at least one formula described herein.

For example, one embodiment provides a method for treating obesity in awarm-blooded animal, comprising administering to said animal in need ofsuch treatment a therapeutically effective amount of at least onecompound according to formula I.

Yet another aspect provides a method for treating narcolepsy in awarm-blooded animal, comprising administering to said animal in need ofsuch treatment a therapeutically effective amount of at least onecompound in accordance with at least one formula described herein.

For example, one embodiment provides a method for treating narcolepsy ina warm-blooded animal, comprising administering to said animal in needof such treatment a therapeutically effective amount of at least onecompound according to formula I.

Another aspect provides a method for treating Alzheimer's disease in awarm-blooded animal, comprising administering to said animal in need ofsuch treatment a therapeutically effective amount of at least onecompound in accordance with at least one formula described herein.

For example, one embodiment provides a method for treating Alzheimer'sdisease in a warm-blooded animal, comprising administering to saidanimal in need of such treatment a therapeutically effective amount ofat least one compound according to formula I.

Another aspect provides a method for treating attention deficithyperactivity disorder in a warm-blooded animal, comprisingadministering to said animal in need of such treatment a therapeuticallyeffective amount of at least one compound in accordance with at leastone formula described herein.

For example, one embodiment provides a method for treating attentiondeficit hyperactivity disorder in a warm-blooded animal, comprisingadministering to said animal in need of such treatment a therapeuticallyeffective amount of at least one compound according to formula I.

Another aspect provides a method for treating a pain disorder in awarm-blooded animal, comprising administering to said animal in need ofsuch treatment a therapeutically effective amount of at least onecompound in accordance with at least one formula described herein.

For example, one embodiment provides a method for treating a paindisorder in a warm-blooded animal, comprising administering to saidanimal in need of such treatment a therapeutically effective amount ofat least one compound according to formula I.

In one embodiment, the warm-blooded animal is a mammalian speciesincluding, but not limited to, for example, humans and domestic animals,such as, for example, dogs, cats, and horses.

In a further embodiment, the warm-blooded animal is a human.

Another aspect provides the use of at least one compound in accordancewith at least one formula described herein in therapy.

For example, one embodiment provides the use of at least one compound inaccordance with formula I in therapy.

Yet an even further embodiment provides the use of a compound inaccordance with at least one formula described herein in the manufactureof a medicament for use in therapy.

As used herein, the term “therapy” also includes “prophylaxis” unlessspecifically indicated to the contrary.

In yet another embodiment a compound in accordance with at least oneformula described herein, or a pharmaceutical composition or formulationcomprising at least one compound in accordance with at least one formuladescribed herein may be administered concurrently, simultaneously,sequentially or separately with at least one other pharmaceuticallyactive compound selected from the following:

(i) antidepressants, such as, for example, agomelatine, amitriptyline,amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin,duloxetine, escitalopram, fluvoxamine, fluoxetine, gepirone, imipramine,ipsapirone, isocarboxazid, maprotiline, mirtazepine, nortriptyline,nefazodone, paroxetine, phenelzine, protriptyline, ramelteon,reboxetine, robalzotan, selegiline, sertraline, sibutramine,thionisoxetine, tranylcypromaine, trazodone, trimipramine, venlafaxine,and equivalents and pharmaceutically active isomer(s) and metabolite(s)thereof;

(ii) antipsychotics, such as, for example, amisulpride, aripiprazole,asenapine, benzisoxidil, bifeprunox, carbamazepine, clozapine,chlorpromazine, debenzapines, dibenzapine, divalproex, droperidol,fluphenazine, haloperidol, iloperidone, loxapine, mesoridazine,molindone, olanzapine, paliperidone, perphenazine, phenothiazine,phenylbutylpiperidine, pimozide, prochlorperazine, quetiapine,risperidone, sertindole, sulpiride, suproclone, thioridazine,thiothixene, trifluoperazine, trimetozine, valproate, valproic acid,zotepine, ziprasidone, and equivalents and pharmaceutically activeisomer(s) and metabolite(s) thereof;

(iii) anxiolytics, such as, for example, alnespirone, azapirones,benzodiazepines, and barbiturates, such as, for example, adinazolam,alprazolam, balezepam, bentazepam, bromazepam, brotizolam, buspirone,clonazepam, clorazepate, chlordiazepoxide, cyprazepam, diazepam,estazolam, fenobam, flunitrazepam, flurazepam, fosazepam, lorazepam,lormetazepam, meprobamate, midazolam, nitrazepam, oxazepam, prazepam,quazepam, reclazepam, suriclone, tracazolate, trepipam, temazepam,triazolam, uldazepam, zolazepam, and equivalents and pharmaceuticallyactive isomer(s) and metabolite(s) thereof;

(iv) anticonvulsants, such as, for example, carbamazepine,oxcarbazepine, valproate, lamotrogine, gabapentin, topiramate,phenytoin, ethosuximide, and equivalents and pharmaceutically activeisomer(s) and metabolite(s) thereof;

(v) Alzheimer's therapies, such as, for example, donepezil, galantamine,memantine, rivastigmine, tacrine, and equivalents and pharmaceuticallyactive isomer(s) and metabolite(s) thereof;

(vi) Parkinson's therapies and agents for the treatment ofextrapyramidal symtpoms, such as, for example, levodopa, carbidopa,amantadine, pramipexole, ropinirole, pergolide, cabergoline,apomorphine, bromocriptine, MAOB inhibitors (i.e. selegine andrasagiline), COMT inhibitors (i.e. entacapone and tolcapone), alpha-2inhibitors, anticholinergics (i.e., benztropine, biperiden,orphenadrine, procyclidine, and trihexyphenidyl), dopamine reuptakeinhibitors, NMDA antagonists, Nicotine agonists, Dopamine agonists, andinhibitors of neuronal nitric oxide synthase, and equivalents andpharmaceutically active isomer(s) and metabolite(s) thereof;

(vii) migraine therapies, such as, for example, almotriptan, amantadine,bromocriptine, butalbital, cabergoline, dichloralphenazone, eletriptan,frovatriptan, lisuride, naratriptan, pergolide, pramipexole,rizatriptan, ropinirole, sumatriptan, zolmitriptan, zomitriptan, andequivalents and pharmaceutically active isomer(s) and metabolite(s)thereof;

(viii) stroke therapies, such as, for example, abciximab, activase,NXY-059, citicoline, crobenetine, desmoteplase, repinotan, traxoprodil,and equivalents and pharmaceutically active isomer(s) and metabolite(s)thereof;

(ix) urinary incontinence therapies, such as, for example, darafenacin,dicyclomine, falvoxate, imipramine, desipramine, oxybutynin,propiverine, propanthedine, robalzotan, solifenacin, alfazosin,doxazosin, terazosin, tolterodine, and equivalents and pharmaceuticallyactive isomer(s) and metabolite(s) thereof;

(x) neuropathic pain therapies, such as, for example, gabapentin,lidoderm, pregablin, and equivalents and pharmaceutically activeisomer(s) and metabolite(s) thereof;

(xi) nociceptive pain therapies, such as, for example, celecoxib,codeine, diclofenac, etoricoxib, fentanyl, hydrocodone, hydromorphone,levo-alpha-acetylmethadol, loxoprofen, lumiracoxib, meperidine,methadone, morphine, naproxen, oxycodone, paracetamol, propoxyphene,rofecoxib, sufentanyl, valdecoxib, and equivalents and pharmaceuticallyactive isomer(s) and metabolite(s) thereof;

(xii) insomnia therapies and sedative hypnotics, such as, for example,agomelatine, allobarbital, alonimid, amobarbital, benzoctamine,butabarbital, capuride, chloral hydrate, clonazepam, chlorazepate,cloperidone, clorethate, dexclamol, estazolam, eszopiclone,ethchlorvynol, etomidate, flurazepam, glutethimide, halazepam,hydroxyzine, mecloqualone, melatonin, mephobarbital, methaqualone,midaflur, midazolam, nisobamate, pagoclone, pentobarbital, perlapine,phenobarbital, propofol, quazepam, ramelteon, roletamide, suproclone,temazepam, triazolam, triclofos, secobarbital, zaleplon, zolpidem,zopiclone and equivalents and pharmaceutically active isomer(s) andmetabolite(s) thereof;

(xiii) mood stabilizers, such as, for example, carbamazepine,divalproex, gabapentin, lamotrigine, lithium, olanzapine,oxycarbazepine, quetiapine, valproate, valproic acid, verapamil, andequivalents and pharmaceutically active isomer(s) and metabolite(s)thereof;

(xiv) obesity therapies, such as, for example, anti-obesity drugs thataffect energy expenditure, glycolysis, gluconeogenesis, glucogenolysis,lipolysis, lipogenesis, fat absorption, fat storage, fat excretion,hunger and/or satiety and/or craving mechanisms, appetite/motivation,food intake, and G-I motility; very low calorie diets (VLCD); andlow-calorie diets (LCD);

(xv) therapeutic agents useful in treating obesity associated disorders,such as, for example, biguanide drugs, insulin (synthetic insulinanalogues) and oral antihyperglycemics (these are divided into prandialglucose regulators and alpha-glucosidase inhibitors), PPAR modulatingagents, such as, for example, PPAR alpha and/or gamma agonists;sulfonylureas; cholesterol-lowering agents, such as, for example,inhibitors of HMG-CoA reductase (3-hydroxy-3-methylglutaryl coenzyme Areductase); an inhibitor of the ileal bile acid transport system (IBATinhibitor); a bile acid binding resin; bile acid sequestering agent,such as, for example, colestipol, cholestyramine, or cholestagel; a CETP(cholesteryl ester transfer protein) inhibitor; a cholesterol absorptionantagonist; a MTP (microsomal transfer protein) inhibitor; a nicotinicacid derivative, including slow release and combination products; aphytosterol compound; probucol; an anti-coagulant; an omega-3 fattyacid; an anti-obesity therapy, such as, for example, sibutramine,phentermine, orlistat, bupropion, ephedrine, and thyroxine; anantihypertensive, such as, for example, an angiotensin converting enzyme(ACE) inhibitor, an angiotensin II receptor antagonist, an adrenergicblocker, an alpha adrenergic blocker, a beta adrenergic blocker, a mixedalpha/beta adrenergic blocker, an adrenergic stimulant, calcium channelblocker, an AT-1 blocker, a saluretic, a diuretic, and a vasodilator; amelanin concentrating hormone (MCH) modulator; an NPY receptormodulator; an orexin receptor modulator; a phosphoinositide-dependentprotein kinase (PDK) modulator; modulators of nuclear receptors, suchas, for example, LXR, FXR, RXR, GR, ERRα, β, PPARα, β, γ and RORalpha; amonoamine transmission-modulating agent, such as, for example, aselective serotonin reuptake inhibitor (SSRI), a noradrenaline reuptakeinhibitor (NARI), a noradrenaline-serotonin reuptake inhibitor (SNRI), amonoamine oxidase inhibitor (MAOI), a tricyclic antidepressive agent(TCA), a noradrenergic and specific serotonergic antidepressant (NaSSA);a serotonin receptor modulator; a leptin/leptin receptor modulator; aghrelin/ghrelin receptor modulator; a DPP-IV inhibitor; and equivalentsand pharmaceutically active isomer(s), metabolite(s), andpharmaceutically acceptable salts, solvates, and prodrugs thereof.

(xvi) agents for treating ADHD, such as, for example, amphetamine,methamphetamine, dextroamphetamine, atomoxetine, methylphenidate,dexmethylphenidate, modafinil, and equivalents and pharmaceuticallyactive isomer(s) and metabolite(s) thereof; and

(xvii) agents used to treat substance abuse disorders, dependence, andwithdrawal, such as, for example, nicotine replacement therapies (i.e.,gum, patches, and nasal spray); nicotinergic receptor agonists, partialagonists, and antagonists, (e.g. varenicline); acomprosate, bupropion,clonidine, disulfiram, methadone, naloxone, naltrexone, and equivalentsand pharmaceutically active isomer(s) and metabolite(s) thereof.

When employed in combination with at least one compound in accordancewith at least one formula described herein, the above otherpharmaceutically active compound may be used, for example, in theamounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art.

Compound(s) in accordance with the formula described herein may beadministered by any means suitable for the condition to be treated,which can depend on the quantity of the compound in accordance theformula described herein to be delivered.

Compound(s) in accordance with the formula described herein may beadministered in the form of a conventional pharmaceutical composition byany route including, but not limited to, for example, orally,intramuscularly, subcutaneously, topically, intranasally, epidurally,intraperitoneally, intrathoracially, intravenously, intrathecally,intracerebroventricularly, and injecting into the joints.

In one embodiment, the route of administration is orally, intravenouslyor intramuscularly.

An “effective amount” of a compound in accordance with the formuladescribed herein may be determined by one of ordinary skill in the art,and includes exemplary dosage amounts for a mammal of from about 0.05 toabout 300 mg/kg/day, preferably less than about 200 mg/kg/day, in asingle dose or in or in the form of individual divided doses. Exemplarydosage amounts for an adult human are from about 1 to 100 (for example,15) mg/kg of body weight of active compound per day, which can beadministered in a single dose or in the form of individual divideddoses, such as from 1 to 4 times per day.

The specific dose level and frequency of dosage for any particularsubject, however, may vary and generally depends on a variety offactors, including, but not limited to, for example, the bioavailabilityof the compound(s) in accordance with the formula described herein inthe administered form; metabolic stability and length of action of thethe compound(s) in accordance with the formula described herein;species, age, body weight, general health, sex, and diet of the subject;mode and time of administration; rate of excretion; drug combination;and severity of the particular condition.

One aspect provides a pharmaceutical composition comprising at least onecompound in accordance with at least formula described herein and atleast one pharmaceutically-acceptable carrier and/or diluent.

For example, one embodiment provides a pharmaceutical compositioncomprising at least one compound in accordance with formula I and atleast one pharmaceutically-acceptable carrier and/or diluent.

Another embodiment provides a method for treating at least one disorderselected from cognitive deficit in schizophrenia, narcolepsy, obesity,attention deficit hyperactivity disorder, and Alzheimer's disease in awarm-blooded animal, comprising administering to said animal in need ofsuch treatment a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound according to at least one formuladescribed herein, and at least one pharmaceutically-acceptable carrierand/or diluent.

Acceptable solid pharmaceutical compositions include, but are notlimited to, for example, powders, tablets, dispersible granules,capsules, cachets, and suppositories.

In a solid pharmaceutical composition, pharmaceutically acceptablecarriers include, but are not limited to, for example, at least onesolid, at least one liquid, and mixtures thereof. The solid carrier canalso be a diluent, flavoring agent, solubilizer, lubricant, suspendingagent, binder, encapsulating material, and/or table disintegratingagent. Suitable carriers, include, but are not limited to, for example,magnesium carbonate; magnesium stearate; talc; lactose; sugar; pectin;dextrin; starch; tragacanth; methyl cellulose; sodium carboxymethylcellulose; a low-melting wax; cocoa butter; and mixtures thereof.

A powder can be prepared by, for example, mixing a finely divided solidwith at least one finely divided compound of at least one formuladescribed herein.

A tablet can be prepared by, for example, mixing at least one compoundof at least one formula described herein in suitable proportions with apharmaceutically acceptable carrier having the necessary bindingproperties and compacted into the desired shape and size.

A suppository can be prepared by, for example, mixing at least onecompound of at least one formula described herein with at least onesuitable non-irritating excipient that is liquid at rectal temperaturebut solid at a temperature below rectal temperature, wherein thenon-irritating excipient is first melted and at least one compound inaccordance with at least one formula described herein is dispersedtherein. The molten homogeneous mixture in then poured into convenientsized molds and allowed to cool and solidify. Exemplary non-irritatingexcipients include, but are not limited to, for example, cocoa butter;glycerinated gelatin; hydrogenated vegetable oils; mixtures ofpolyethylene glycols of various molecular weights; and fatty acid estersof polyethylene glycol.

Acceptable liquid pharmaceutical compositions include, but are notlimited to, for example, solutions, suspensions, and emulsions. Forexample, sterile water or water propylene glycol solutions of at leastone compound of at least one formula described herein are liquidpharmaceutical compositions suitable for parenteral administration.Liquid compositions can also be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions for oral administration can be prepared by dissolvingat least one compound in accordance with at least one formula describedherein in water and adding suitable colorants, flavoring agents,stabilizers, and/or thickening agents as desired.

Aqueous suspensions for oral administration can be prepared bydispersing at least one finely divided compound of at least one formuladescribed herein in water together with a viscous material, such as, forexample, a natural synthetic gum, resin, methyl cellulose, and sodiumcarboxymethyl cellulose.

In one embodiment, the pharmaceutical composition contains from about0.05% to about 99% w (percent by weight) of at least one compound inaccordance with at least one formula described herein. All percentagesby weight being based on total composition.

In another embodiment, the pharmaceutical composition contains fromabout 0.10% to about 50% w (percent by weight) of at least one compoundin accordance with at least one formula described herein. Allpercentages by weight being based on total composition.

Another embodiment, provides a pharmaceutical composition comprising acompound of at least one formula described herein, and apharmaceutically acceptable carrier/diluent for therapy.

Further, there is provided a pharmaceutical composition comprising acompound of at least one formula described herein, in association with apharmaceutically acceptable carrier use in any of the conditionsdiscussed above.

In a further aspect, the present invention provides a method ofpreparing a compound of at least one formula described herein.

Biological Evaluation

At least one compound of at least one formula described herein includingthe compounds described in the Examples hereof, when tested in at leastone in vitro assay as substantially described below is active towards H3receptors. Particularly, at least one compound described herein is aneffective H3 receptor ligand. The in vitro activity may be related to invivo activity but may not be linearly correlated with binding affinity.In the in vitro assay, a compound can be tested for its activity towardH3 receptors and IC₅₀ obtained to determine the activity for aparticular compound toward the H3 receptor.

Guanosine 5′-O-(3-[³⁵S]thio)triphosphate [GTPγS] Binding Assay

A GTPγS binding assay can be used to investigate antagonist propertiesof compounds in CHO cells (Chinese Hamster Ovary) transfected with humanHistamine H3 receptor (hH3R). Membranes from CHO cells expressing hH3R(10 g/well) are diluted in GTPγS assay buffer (20 mM Hepes, 10 mM MgCl₂,100 mM NaCl, pH 7.4) and preincubated with saponine (3 μg/ml), GDP (10μM) and PVT-WGA SPA beads (125 μg/well) (Amersham) for 30 minutes. Todetermine antagonist activity, (R)-α-methyl histamine (30 nM) is addedin 96 well SPA plate with [³⁵S]GTPγS (0.2 nM) and various concentrationof H3R antagonists. The GTPγS binding assay is started with addition ofthe mixture membrane/saponine/GDP and incubated for 90 minutes at roomtemperature. The amount of bound [³⁵S]GTPγS is determined by using theMicroBeta Trilux counter (PerkinElmer). The percentage of [³⁵S]GTPγSbound in each sample is calculated as a percentage of that bound controlsample incubated in absence of H3 antagonist. Duplicate determinationsare obtained for each concentration, and the data are analyzed usingExcelFit4 to obtain the IC₅₀.

IC₅₀ Values

At least one formula compound in accordance with the present disclosuremay have an IC₅₀ value of less than about 1 μM. In a further embodiment,at least one compound of at least one formula described herein may haveactivity in at least one of the above referenced assays via an IC₅₀value of between about 1 nm to about 1 μM. In an even furtherembodiment, at least one compound of at least one formula describedherein may have activity in at least one of the above referenced assaysvia an IC₅₀ value of between about 2 nM to about 100 nM. In yet afurther embodiment, at least one compound of at least one formuladescribed herein may have activity in at least one of the abovereferenced assays via an IC₅₀ value of between about 2 nM and 50 nM. Inone embodiment, at least one compound of at least one formula describedherein may have activity in at least one of the above referenced assaysvia an IC₅₀ value of less than about 100 nM. In another embodiment, atleast one compound of at least one formula described herein may haveactivity in at least one of the above referenced assays via an IC₅₀value of less than about 50 nM. In yet another embodiment, at least onecompound of at least one formula described herein may have activity inat least one of the above referenced assays via an IC₅₀ value of lessthan about 20 nM.

Set forth in Table 1 hereinbelow for the Example 1-34 compounds are IC₅₀values that were generated in accordance with the GTPγS Binding Assay asessentially described hereinabove.

TABLE 1 GTPγS Binding Example No. IC₅₀ (nM) 1 7.481 2 5.655 3 326.5 413.54 5 8.536 6 >1111 7 8.817 8 4.943 9 121.2 10 8.064 11 5.767 12 132513 29.07 14 15.29 15 139.9 16 >1111 17 14.24 18 5.981 19 1272 20 8.73621 6.826 22 1009 23 >1111 24 15.85 25 12.01 26 >1111 27 12.03 28 5.28129 575.9 30 16.32 31 6.962 32 >1111 33 41.01 34 51.8

INCORPORATION BY REFERENCE

Incorporated by reference herein in their entireties are U.S.Provisional Patent Application No. 61/305,581, filed Feb. 18, 2010,entitled Solid Forms Comprising A Cyclopropyl Amide Derivative; and U.S.Patent Application No. 61/305,583, filed Feb. 18, 2010, entitledProcesses For Making Cyclopropyl Amide Derivatives And IntermeciatesAssociated Therewith.

EXAMPLES

The invention is further defined in the following Examples. It should beunderstood that the Examples are given by way of illustration only. Fromthe above discussion and the Examples, one skilled in the art canascertain the essential characteristics of the invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications to adapt the invention to various uses and conditions.As a result, the invention is not limited by the illustrative examplesset forth hereinbelow, but rather defined by the claims appended hereto.

All temperatures are in degrees Celsius (° C.) and are uncorrected.

Unless otherwise noted, commercial reagents used in preparing theexample compounds were used as received without additional purification.

Unless otherwise noted, the solvents used in preparing the examplecompounds were commercial anhydrous grades and were used without furtherdrying or purification.

All starting materials are commercially available, unless statedotherwise.

The names of the products were determined using the naming softwareincluded in CambridgeSoft E-Notebook version 9.2 (Chemoffice 9.0.7).

The following abbreviations are employed herein: aq.: aqueous; br.:broad; Bu: butyl; calcd: calculated; Celite®: brand of diatomaceousearth filtering agent, registered trader of Celite Corporation; d:doublet; dd: doublet of doublet; ddd: doublet of doublet of doublet;dddd: doublet of doublet of doublet of doublet; DABCO:1,4-diazabicyclo[2.2.2]octane; DCE: dichloroethane; DCM:dichloromethane; DIPEA: N-ethyl-N-isopropylpropan-2-amine; DME: dimethylether; DMEA: dimethyl ethylamine; DMF: N,N-dimethyl formamide; DMSO:dimethyl sulfoxide; dq: doublet of quartet; dt: doublet of triplet; EDC:1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride; ESI:electrospray ion source; EtOAc: ethyl acetate; EtOH: ethanol; g: gram;h: hour(s); ¹H NMR: proton nuclear magnetic resonance; HBTU:O-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate;HOBT: N-Hydroxybenzotriazole; HPLC: high pressure liquid chromatography;HRMS: high resolution mass spectrometry; iPrOH: iso-propanol; L: liter;m: multiplet; M: molar; mL: milliliter; MeOH: methanol; mg: milligram;MgSO₄: anhydrous magnesium sulfate (drying agent); MHz: megahertz; min:minute(s); mmol: millimole; mol: mole; MPLC: medium pressure liquidchromatography; MS: mass spectrometry; MTBE: methyl tert-butyl ether;NaHCO₃: sodium bicarbonate; NH₄Cl: ammonium chloride; ppm: parts permillion; q: quartet; quin: quintet; rt: room temperature; s: singlet;sat: saturated; t: triplet; TEA: triethylamine; tBuOH: tert-butanol; td:triplet of doublet; TFA: trifluoroacetic acid; and THF: tetrahydrofuran.

Column chromatography was performed using 32-63 micron, 60 Å, silica gelwith glass column and air pressure. MPLC was performed on an ISCOCompanion instrument using pre-packaged disposable RediSep SiO₂stationary phase at 5-100 mL/min, UV detection (190-760 nm range).

The mass spectra were recorded using electrospray (LC-MS; method A:column XTerra MS C8 2.5 μm 2.1×30 mm, buffer gradient H₂O 0.1% TFA:CH₃CN+0.04% TFA, MS: micromass ZMD/ammonium acetate buffer; method B:Agilent Zorbax SB-C8 column 1.8 m, 2.1×30 mm, H₂O with 0.1% formic acid:MeCN with 0.05% formic acid) ionisation techniques. Alternatively, massspectra were recorded on a Waters MS consisting of an Alliance 2795 (LC)and Waters Micromass ZQ detector at 120° C. The mass spectrometer wasequipped with an electrospray ion source (ESI) operated in a positive ornegative ion mode. The mass spectrometer was scanned between m/z100-1000 with a scan time of 0.3 s.

The ¹H NMR spectra were recorded on Varian NMR Spectrometer at 400 MHzor Varian Mercury 300 MHz. The ¹H NMR spectra were interpreted using theprocessing software ACD/SpecManager version 10.02. Alternatively, theywere recorded on a Bruker UltraShield Advance 400 MHz/54 mm spectrometerand processed with XWIN-NMR version 2.6 software. The chemical shifts(δ) are reported in parts-per-million from a tetramethylsilane internalstandard.

Example 14-(trans-2-((R)-4-isopropyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,diastereomeric mixture

Intermediate 20 (655 mg, 2.28 mmol) was dissolved in DCE (20 mL). TEA(1.589 mL, 11.40 mmol) was added, followed by propan-2-one (0.338 mL,4.56 mmol) and sodium triacetoxyborohydride (725 mg, 3.42 mmol). Thereaction mixture was stirred overnight and washed with sat. NaHCO₃. Theorganic layer was dried over MgSO₄, filtered and concentrated underreduced pressure. The crude material was purified on preparative HPLC MSusing the short high pH shallow gradient method (Mobile phase: 20-40% B;A: H₂O with 10 mM NH₄CO₃ and 0.375% NH₄OH v/v, B: CH₃CN, 10 min run) onXBridge Prep C18 OBD, 30×50 mm, 5 μm, Waters reverse phase column,providing 332 mg title compound (44.1%) as a solid (diastereomericmixture). ¹H NMR (400 MHz, CD₃OD) δ ppm 1.03 (dd, J=8.98, 6.64 Hz, 6H)1.25 (d, J=6.64 Hz, 2H) 1.37 (br. s., 2H) 1.60 (ddd, J=9.28, 5.18, 4.30Hz, 1H) 2.16 (br. s., 1H) 2.22-2.36 (m, 2H) 2.43 (br. s., 1H) 2.62-2.72(m, 1H) 2.75 (d, J=11.33 Hz, 1H) 2.86 (dd, J=10.94, 2.73 Hz, 1H)2.90-3.05 (m, 0.5H) 3.34-3.48 (m, 0.5H) 3.92-4.11 (m, 0.5H) 4.21-4.34(m, 1H) 4.57-4.73 (m, 0.5H) 7.26 (d, J=8.20 Hz, 2H) 7.80 (d, J=8.59 Hz,2H); HRMS m/z calcd for C₁₉H₂₈N₃O₂ 330.21760 [M+H]⁺. found 330.21773.

Example 24-(trans-2-((R)-4-isopropyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 1

Example 1 (304.0 mg, 0.92 mmol) (diastereomeric mixture) was separatedon a MettlerToledo Minigram Supercritical Fluid Chromatographyinstrument using the following conditions: ChiralPak AD-H, 10×250 mm, 5μm particle size, 10.0 mL/min, mobile phase: 55% EtOH with 0.1% DMEA,supercritical CO₂, regulator set to 100 Bar, column temperature set to35° C., UV 215 nm, providing 120 mg isomer 1 (39.4%) and 104 mg isomer 2(34.1%) as solids. The product was analyzed on chiral SFC (UV detection)using isocratic method (mobile phase: 55% EtOH with 0.1% DMEA,supercritical CO₂) on Chiral Pak AD-H, 10×250 mm, 5 μm particle size,giving an enantiomeric purity of 99%, R_(t) 1.81 min (isomer 1) and 3.78min (isomer 2). Isomer 1: ¹H NMR (400 MHz, CD₃OD) δ ppm 1.02 (d, J=6.64Hz, 3H) 1.02 (d, J=6.64 Hz, 3H) 1.25 (br. s., 1H) 1.37 (br. s., 3H)1.52-1.67 (m, 1H) 2.07-2.36 (m, 3H) 2.42 (br. s., 1H) 2.67 (d, J=6.64Hz, 1H) 2.75 (dt, J=11.33, 1.76 Hz, 1H) 2.85 (dddd, J=11.38, 3.37, 1.95,1.66 Hz, 1H) 2.97 (t, J=12.89 Hz, 0.5H) 3.37 (t, J=11.33 Hz, 0.5H) 4.03(d, J=11.33 Hz, 0.5H) 4.30 (d, J=12.89 Hz, 0.5H) 4.37 (br. s., 0.5H)4.64 (br. s., 0.5H) 7.26 (d, J=8.20 Hz, 2H) 7.80 (d, J=8.20 Hz, 2H);HRMS m/z calcd for C₁₉H₂₈N₃O₂ 330.21760 [M+H]⁺. found 330.21731;[α]_(D)+156.8° (c 0.91, MeOH).

Example 34-(trans-2-((R)-4-isopropyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 2

This isomer was isolated in accordance with the chiral separationdescribed in Example 2 and treated as described therein. The product wasanalyzed on chiral SFC (UV detection) using isocratic method (mobilephase: 55% EtOH with 0.1% DMEA, supercritical CO₂) on ChiralPak AD-H,10×250 mm, 5 μm particle size, giving an enantiomeric purity of 99%,R_(t) 1.81 min (isomer 1) and 3.78 min (isomer 2). Isomer 2: ¹H NMR (400MHz, CD₃OD) δ ppm 1.04 (d, J=6.64 Hz, 6H) 1.25 (d, J=7.03 Hz, 3H) 1.37(br. s., 1H) 1.50-1.73 (m, 1H) 2.17 (t, J=10.94 Hz, 1H) 2.23-2.49 (m,3H) 2.59-2.72 (m, 1H) 2.76 (d, J=11.33 Hz, 1H) 2.84 (t, J=9.77 Hz, 1H)2.91-3.10 (m, 0.5H) 3.42 (t, J=11.52 Hz, 0.5H) 3.97 (d, J=14.84 Hz,0.5H) 4.27 (d, J=12.11 Hz, 0.5H) 4.43 (br. s., 0.5H) 4.66 (br. s., 0.5H)7.26 (d, J=8.59 Hz, 2H) 7.80 (d, J=8.20 Hz, 2H); HRMS m/z calcd forC₁₉H₂₈N₃O₂ 330.21760 [M+H]⁺. found 330.21745; [α]_(D)−234° (c 1.22,MeOH).

Example 44-(trans-2-((S)-4-isopropyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,diastereomeric mixture

Intermediate 21 (584 mg, 2.03 mmol) was dissolved in DCE (20 mL). TEA(1.416 mL, 10.16 mmol) was added, followed by propan-2-one (0.301 mL,4.06 mmol) and sodium triacetoxyborohydride (646 mg, 3.05 mmol). Thereaction mixture was stirred overnight and washed with sat NaHCO₃. Theorganic layer was dried over MgSO₄, filtered and concentrated underreduced pressure. The crude material was purified on preparative HPLC MSusing the short high pH shallow gradient method (Mobile phase: 20-40% B;A: H₂O with 10 mM NH₄CO₃ and 0.375% NH₄OH v/v, B: CH₃CN, 10 min run) onXBridge Prep C18 OBD, 30×50 mm, 5 μm, Waters reverse phase column,providing 299 mg title compound (44.6%) as a solid (diastereomericmixture). ¹H NMR (400 MHz, CD₃OD) δ ppm 1.03 (dd, J=8.98, 6.64 Hz, 6H)1.25 (d, J=7.03 Hz, 2H) 1.37 (br. s., 2H) 1.51-1.67 (m, 1H) 2.10-2.49(m, 4H) 2.62-2.72 (m, 1H) 2.75 (d, J=11.33 Hz, 1H) 2.80-2.90 (m, 1H)2.91-3.04 (m, 0.5H) 3.33-3.50 (m, 0.5H) 3.91-4.10 (m, 0.5H) 4.19-4.50(m, 1H) 4.58-4.72 (m, 0.5H) 7.26 (d, J=8.20 Hz, 2H) 7.80 (d, J=8.59 Hz,2H); HRMS m/z calcd for C₁₉H₂₈N₃O₂ 330.21760 [M+H]⁺. found 330.21763.

Example 54-(trans-2-((S)-4-isopropyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 1

Example 4 (265.15 mg, 0.80 mmol) (diastereomeric mixture) was separatedon a MettlerToledo Minigram Supercritical Fluid Chromatographyinstrument using the following conditions: ChiralPak AD-H, 10×250 mm, 5μm particle size, 10.0 mL/min, mobile phase: 45% EtOH with 0.1% DMEA,supercritical CO₂, regulator set to 100 Bar, column temperature set to35° C., UV 215 nm, providing 113 mg isomer 1 (42.5%) and 114 mg isomer 2(42.8%) as solids. The product was analyzed on chiral SFC (UV detection)using isocratic method (mobile phase: 55% EtOH with 0.1% DMEA,supercritical CO₂) on Chiral Pak AD-H, 10×250 mm, 5 μm particle size,giving an enantiomeric purity of 99%, R_(t) 1.85 min (isomer 1) and 2.43min (isomer 2). Isomer 1: ¹H NMR (400 MHz, CD₃OD) δ ppm 1.02 (d, J=6.64Hz, 3H) 1.04 (d, J=6.64 Hz, 3H) 1.25 (d, J=6.64 Hz, 3H) 1.37 (br. s.,1H) 1.52-1.69 (m, 1H) 2.17 (t, J=11.33 Hz, 1H) 2.28 (br. s., 2H) 2.40(d, J=8.98 Hz, 1H) 2.67 (septuplet, J=6.25 Hz, 1H) 2.76 (d, J=11.72 Hz,1H) 2.84 (t, J=10.55 Hz, 1H) 2.92-3.04 (m, 0.5H) 3.38-3.48 (m, 0.5H)3.97 (d, J=12.11 Hz, 0.5H) 4.27 (d, J=13.67 Hz, 0.5H) 4.43 (br. s.,0.5H) 4.66 (br. s., 0.5H) 7.26 (d, J=8.59 Hz, 2H) 7.78-7.83 (m, 2H);HRMS m/z calcd for C₁₉H₂₈N₃O₂ 330.21760 [M+H]⁺. found 330.21708;[α]_(D)+256.3° (c 1.85, MeOH).

Example 64-(trans-2-((S)-4-isopropyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 2

This isomer was isolated in accordance with the chiral separationdescribed in Example 5 and treated as described therein. The product wasanalyzed on chiral SFC (UV detection) using isocratic method (mobilephase: 55% EtOH with 0.1% DMEA, supercritical CO₂) on ChiralPak AD-H,10×250 mm, 5 μm particle size, giving an enantiomeric purity of 99%,R_(t) 1.85 min (isomer 1) and 2.43 min (isomer 2). Isomer 2: ¹H NMR (400MHz, CD₃OD) δ ppm 1.02 (d, J=6.64 Hz, 3H) 1.05 (d, J=6.64 Hz, 3H)1.16-1.28 (m, 1H) 1.29-1.47 (m, 3H) 1.53-1.66 (m, 1H) 2.07-2.37 (m, 3H)2.42 (br. s., 1H) 2.67 (septuplet, J=6.64 Hz, 1H) 2.75 (dt, J=11.43,1.90 Hz, 1H) 2.80-2.91 (m, 1H) 2.91-3.08 (m, 0.5H) 3.32-3.45 (m, 0.5H)4.03 (d, J=13.67 Hz, 0.5H) 4.30 (d, J=12.50 Hz, 0.5H) 4.37 (br. s.,0.5H) 4.64 (br. s., 0.5H) 7.26 (d, J=8.20 Hz, 2H) 7.80 (d, J=8.20 Hz,2H); HRMS m/z calcd for C₁₉H₂₈N₃O₂ 330.21760 [M+H]⁺. found 330.21694;[α]_(D)−153.6° (c 0.92, MeOH).

Example 74-(trans-2-((R)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,diastereomeric mixture

Intermediate 20 was dissolved in DCE (13.0 mL). TEA (0.958 mL, 6.87mmol) was added, followed by cyclobutanone (193 mg, 2.75 mmol) andsodium triacetoxyborohydride (437 mg, 2.06 mmol). The reaction mixturewas stirred overnight and washed with sat. NaHCO₃. The organic layer wasdried over MgSO₄, filtered and concentrated under reduced pressure. Thecrude material was purified on preparative HPLC MS using the short highpH shallow gradient method (Mobile phase: 20-40% B; A: H₂O with 10 mMNH₄CO₃ and 0.375% NH₄OH v/v, B: CH₃CN, 10 min run) on XBridge Prep C18OBD, 30×50 mm, 5 μm, Waters reverse phase column, providing 159 mg titlecompound (33.9%) as a solid (diastereomeric mixture). ¹H NMR (400 MHz,CD₃OD) δ ppm 1.27 (d, J=7.03 Hz, 2H) 1.39 (br. s., 2H) 1.59 (ddd,J=9.18, 5.27, 4.30 Hz, 1H) 1.65-1.78 (m, 3H) 1.78-1.98 (m, 3H) 1.98-2.10(m, 2H) 2.20-2.34 (m, 1H) 2.42 (br. s., 1H) 2.62-2.77 (m, 2H) 2.78-2.90(m, 1H) 2.90-3.05 (m, 1H) 3.94-4.10 (m, 1H) 4.23-4.35 (m, 1H) 7.25 (d,J=8.59 Hz, 2H) 7.80 (d, J=8.20 Hz, 2H); HRMS m/z calcd for C₂₀H₂₈N₃O₂342.21760 [M+H]⁺. found 342.21804.

Example 84-((trans)-2-((R)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 1

Example 7 (138 mg, 0.40 mmol) (diastereomeric mixture) was separated ona MettlerToledo Minigram Supercritical Fluid Chromatography instrumentusing the following conditions: ChiralPak AD-H, 10×250 mm, 5 μm particlesize, 10.0 mL/min, mobile phase: 55% iPrOH with 0.1% DMEA, supercriticalCO₂, regulator set to 100 Bar, column temperature set to 35° C., UV 215nm, providing 57.8 mg isomer 1 (41.9%) and 56.5 mg isomer 2 (41.0%) assolids. The product was analyzed on chiral SFC (UV detection) usingisocratic method (mobile phase: 55% EtOH with 0.1% DMEA, supercriticalCO₂) on ChiralPak AD-H, 10×250 mm, 5 μm particle size, giving anenantiomeric purity of 99%, R_(t) 1.92 min (isomer 1) and 3.46 min(isomer 2). Isomer 1: ¹H NMR (400 MHz, CD₃OD) δ ppm 1.26 (br. s., 1H)1.38 (br. s., 3H) 1.59 (ddd, J=9.57, 4.69, 4.49 Hz, 1H) 1.65-1.77 (m,3H) 1.77-1.98 (m, 3H) 1.98-2.09 (m, 2H) 2.22-2.31 (m, 1H) 2.43 (br. s.,1H) 2.63-2.74 (m, 2H) 2.84 (d, J=11.33 Hz, 1H) 2.96 (t, J=12.89 Hz,0.5H), 3.36 (t, J=12.30 Hz, 0.5H) 4.04 (d, J=12.11 Hz, 0.5H) 4.31 (d,J=12.11 Hz, 0.5H) 4.38 (br. s., 0.5H) 4.65 (br. s., 0.5H) 7.25 (d,J=8.20 Hz, 2H), 7.80 (d, J=8.20 Hz, 2H); HRMS m/z calcd for C₂₀H₂₈N₃O₂342.21760 [M+H]⁺. found 342.21771; [α]_(D)+156.3° (c 2.20, MeOH).

Example 94-((trans)-2-((R)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 2

This isomer was isolated in accordance with the chiral separationdescribed in Example 8 and treated as described therein. The product wasanalyzed on chiral SFC (UV detection) using isocratic method (mobilephase: 55% EtOH with 0.1% DMEA, supercritical CO₂) on ChiralPak AD-H,10×250 mm, 5 μm particle size, giving an enantiomeric purity of 99%,R_(t) 1.92 min (isomer 1) and 3.46 min (isomer 2). Isomer 2: ¹H NMR (400MHz, CD₃OD) δ ppm 1.27 (d, J=7.03 Hz, 3H) 1.33-1.42 (m, 1H) 1.53-1.65(m, 1H) 1.67-1.77 (m, 3H) 1.78-1.87 (m, 1H) 1.87-1.95 (m, 1H) 1.98-2.07(m, 3H) 2.27 (br. s., 1H) 2.42 (br. s., 1H) 2.63-2.76 (m, 2H) 2.83 (t,J=9.96 Hz, 1H) 2.96 (t, J=12.50 Hz, 0.5H) 3.41 (t, J=11.33 Hz, 0.5H)3.98 (d, J=12.11 Hz, 0.5H) 4.28 (d, J=12.11 Hz, 0.5H) 4.44 (br. s.,0.5H) 4.67 (br. s., 0.5H) 7.25 (d, J=8.20 Hz, 2H) 7.80 (d, J=8.59 Hz,2H); HRMS m/z calcd for C₂₀H₂₈N₃O₂ 342.21760 [M+H]⁺. found 342.21749;[α]_(D)−223.7° (c 2.20, MeOH).

Example 104-(trans-2-((S)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,diastereomeric mixture

Intermediate 21 (478 mg, 1.66 mmol) was dissolved in DCE (15.0 mL). TEA(1.159 mL, 8.32 mmol) was added, followed by cyclobutanone (233 mg, 3.33mmol) and sodium triacetoxyborohydride (529 mg, 2.50 mmol). The reactionmixture was stirred overnight and was washed with sat. NaHCO₃. Theorganic layer was dried over MgSO₄, filtered and concentrated underreduced pressure. The crude material was purified on preparative HPLC MSusing the short high pH shallow gradient method (Mobile phase: 20-40% B;A: H₂O with 10 mM NH₄CO₃ and 0.375% NH₄OH v/v, B: CH₃CN, 10 min run) onXBridge Prep C18 OBD, 30×50 mm, 5 μm, Waters reverse phase column,providing 192 mg title compound (33.8%) as a solid (diastereomericmixture). ¹H NMR (400 MHz, CD₃OD) δ ppm 1.27 (d, J=6.64 Hz, 2H) 1.39(br. s., 2H) 1.59 (ddd, J=9.18, 5.27, 4.30 Hz, 1H) 1.68-1.98 (m, 6H)1.98-2.11 (m, 2H) 2.19-2.35 (m, 1H) 2.42 (br. s., 1H) 2.62-2.77 (m, 2H)2.77-2.90 (m, 1H) 2.90-3.06 (m, 1H) 3.92-4.12 (m, 1H) 4.22-4.36 (m, 1H)7.25 (d, J=8.59 Hz, 2H) 7.80 (d, J=7.81 Hz, 2H); HRMS m/z calcd forC₂₀H₂₈N₃O₂ 342.21760 [M+H]⁺. found 342.21783.

Example 114-((trans)-2-((S)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 1

Example 10 (173 mg, 0.51 mmol) (diastereomeric mixture) was separated ona MettlerToledo Minigram Supercritical Fluid Chromatography instrumentusing the following conditions: ChiralPak AD-H, 10×250 mm, 5 μm particlesize, 10.0 mL/min, mobile phase: 40% EtOH with 0.1% DMEA, supercriticalCO₂, regulator set to 100 Bar, column temperature set to 35° C., UV 215nm, providing 73.0 mg isomer 1 (42.2%) and 72.7 mg isomer 2 (42.0%) assolids. The product was analyzed on chiral SFC (UV detection) usingisocratic method (mobile phase: 55% EtOH with 0.1% DMEA, supercriticalCO₂) on Chiral Pak AD-H, 10×250 mm, 5 μm particle size, giving anenantiomeric purity of 99%, R_(t) 1.97 min (isomer 1) and 2.62 min(isomer 2). Isomer 1: ¹H NMR (400 MHz, CD₃OD) δ ppm 1.27 (d, J=7.03 Hz,3H) 1.33-1.42 (m, 1H) 1.53-1.65 (m, 1H) 1.65-1.77 (m, 3H) 1.78-1.97 (m,3H) 1.97-2.09 (m, 2H) 2.27 (br. s., 1H) 2.42 (br. s., 1H) 2.63-2.76 (m,2H) 2.77-2.89 (m, 1H) 2.96 (t, J=12.11 Hz, 0.5H) 3.36-3.48 (m, 0.5H)3.99 (d, J=11.72 Hz, 0.5H) 4.28 (d, J=12.89 Hz, 0.5H) 4.44 (br. s.,0.5H) 4.67 (br. s., 0.5H) 7.25 (d, J=8.20 Hz, 2H) 7.80 (d, J=8.59 Hz,2H); HRMS m/z calcd for C₂₀H₂₈N₃O₂ 342.21760 [M+H]⁺. found 342.21754;[α]_(D)+225.1° (c 2.26, MeOH).

Example 124-((trans)-2-((S)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 2

This isomer was isolated in accordance with the chiral separationdescribed in Example 11 and treated as described therein. The productwas analyzed on chiral SFC (UV detection) using isocratic method (mobilephase: 55% EtOH with 0.1% DMEA, supercritical CO₂) on ChiralPak AD-H,10×250 mm, 5 μm particle size, giving an enantiomeric purity of 99%,R_(t) 1.97 min (isomer 1) and 2.62 min (isomer 2). Isomer 2: ¹H NMR (400MHz, CD₃OD) δ ppm 1.26 (br. s., 1H) 1.31-1.45 (m, 3H) 1.59 (ddd, J=9.18,4.88, 4.69 Hz, 1H) 1.65-1.77 (m, 3H) 1.77-1.87 (m, 1H) 1.87-1.97 (m, 2H)1.98-2.08 (m, 2H) 2.21-2.30 (m, 1H) 2.36-2.49 (m, 1H) 2.63-2.75 (m, 2H)2.84 (d, J=11.33 Hz, 1H) 2.89-3.03 (m, 0.5H) 3.36-3.42 (m, 0.5H)3.97-4.09 (m, 0.5H) 4.25-4.35 (m, 0.5H) 4.35-4.43 (m, 0.5H) 4.58-4.71(m, 0.5H) 7.25 (d, J=8.59 Hz, 2H) 7.80 (d, J=8.20 Hz, 2H); HRMS m/zcalcd for C₂₀H₂₈N₃O₂ 342.21760 [M+H]⁺. found 342.21773; [α]_(D)−158.2°(c 2.90, MeOH).

Example 134-(trans-2-((R)-4-cyclobutyl-2-ethylpiperazine-1-carbonyl)cyclopropyl)benzamide,diastereomeric mixture

Intermediate 22 (335 mg, 1.11 mmol) was dissolved in DCE (10 mL). TEA(0.774 mL, 5.55 mmol) was added, followed by cyclobutanone (156 mg, 2.22mmol) and sodium triacetoxyborohydride (353 mg, 1.67 mmol). The reactionmixture was stirred overnight and concentrated under reduced pressure.The residue was redissolved in DCM, washed with sat. NaHCO₃, dried overMgSO₄, filtered and concentrated under reduced pressure. The crudematerial was purified on preparative HPLC UV using the long high pHshallow gradient method (Mobile phase: 30-50% B; A: H₂O with 10 mMNH₄CO₃ and 0.375% NH₄OH v/v, B: CH₃CN, 30 min run) on XBridge Prep C18OBD, 50×250 mm, 10μ, Waters reverse phase column, providing 309 mg titlecompound (78%) as a solid (diastereomeric mixture). ¹H NMR (400 MHz,CD₃OD) δ ppm 0.69 (t, J=7.62 Hz, 1H) 0.90 (ddd, J=19.34, 7.62, 7.42 Hz,2H) 1.32-1.44 (m, 1H) 1.54-1.63 (m, 1H) 1.63-2.12 (m, 10H) 2.22-2.52 (m,2H) 2.61-2.75 (m, 1H) 2.75-2.95 (m, 3H) 4.02 (br. s., 0.5H) 4.15 (br.s., 0.5H) 4.36 (br. s., 0.5H) 4.48 (br. s., 0.5H) 7.20-7.28 (m, 2H) 7.80(d, J=8.20 Hz, 2H); HRMS m/z calcd for C₂₁H₃₀N₃O₂ 356.23325 [M+H]⁺.found 356.23326.

Example 144-(trans-2-((R)-4-cyclobutyl-2-ethylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 1

Example 13 (150 mg, 0.42 mmol) (diastereomeric mixture) was separated ona MettlerToledo Minigram Supercritical Fluid Chromatography instrumentusing the following conditions: ChiralPak AD-H, 10×250 mm, 5 μm particlesize, 10.0 mL/min, mobile phase: 55% iPrOH with 0.1% DMEA, supercriticalCO₂, regulator set to 100 Bar, column temperature set to 35° C., UV 215nm, providing 69.4 mg isomer 1 (93%) and 69.4 mg isomer 2 (93.0%) assolids. The product was analyzed on chiral SFC (UV detection) usingisocratic method (mobile phase: 55% iPrOH with 0.1% DMEA, supercriticalCO₂) on ChiralPak AD-H, 10×250 mm, 5 μm particle size, giving anenantiomeric purity of 99%, R_(t) 1.80 min (isomer 1) and 2.66 min(isomer 2). Isomer 1: ¹H NMR (400 MHz, CD₃OD) δ ppm 0.90 (dt, J=19.24,7.57 Hz, 3H) 1.32-1.44 (m, 1H) 1.53-1.61 (m, 1H) 1.65-1.86 (m, 6H)1.86-1.98 (m, 2H) 1.98-2.10 (m, 2H) 2.21-2.33 (m, 1H) 2.39-2.53 (m, 1H)2.62-2.74 (m, 1H) 2.78-2.94 (m, 3H) 4.01-4.17 (m, 1H) 4.31-4.51 (m, 1H)7.25 (d, J=7.03 Hz, 2H) 7.80 (d, J=8.20 Hz, 2H); HRMS m/z calcd forC₂₁H₃₀N₃O₂ 356.2333 [M+H]⁺; [α]_(D)+181° (c 0.48, MeOH).

Example 154-(trans-2-((R)-4-cyclobutyl-2-ethylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 2

This isomer was isolated in accordance with the chiral separationdescribed in Example 14 and treated as described therein. The productwas analyzed on chiral SFC (UV detection) using isocratic method (mobilephase: 55% iPrOH with 0.1% DMEA, supercritical CO₂) on ChiralPak AD-H,10×250 mm, 5 μm particle size, giving an enantiomeric purity of 99%,R_(t) 1.80 min (isomer 1) and 2.66 min (isomer 2). Isomer 2: ¹H NMR (400MHz, CD₃OD) δ ppm 0.69 (br. s., 2H) 0.88 (br. s., 1H) 1.37 (br. s., 1H)1.54-2.12 (m, 11H) 2.18-2.48 (m, 2H) 2.67 (br. s., 1H) 2.74-2.94 (m, 3H)3.92-4.22 (m, 1H) 4.28-4.54 (m, 1H) 7.24 (br. s., 2H) 7.79 (br. s., 2H);HRMS m/z calcd for C₂₁H₃₀N₃O₂ 356.2333 [M+H]⁺. found 356.2325;[α]_(D)−209° (c 0.54, MeOH).

Example 164-(trans-2-((S)-4-cyclobutyl-2-ethylpiperazine-1-carbonyl)cyclopropyl)benzamide,diastereomeric mixture

Intermediate 23 (322 mg, 1.07 mmol) was dissolved in DCE (10 mL). TEA(0.746 mL, 5.35 mmol) was added, followed by cyclobutanone (150 mg, 2.14mmol) and sodium triacetoxyborohydride (340 mg, 1.61 mmol). The reactionmixture was stirred overnight and concentrated under reduced pressure.The residue was redissolved in DCM, washed with sat. NaHCO₃, dried overMgSO₄, filtered and concentrated under reduced pressure. The crudematerial was purified on preparative HPLC UV using the long high pHshallow gradient method (Mobile phase: 40-60% B; A: H₂O with 10 mMNH₄CO₃ and 0.375% NH₄OH v/v, B: CH₃CN, 30 min run) on XBridge Prep C18OBD, 50×250 mm, 10μ, Waters reverse phase column, providing 294 mg titlecompound (77%) as a white solid (diastereomeric mixture). ¹H NMR (400MHz, CD₃OD) δ ppm 0.69 (t, J=7.62 Hz, 1H) 0.90 (dt, J=19.24, 7.57 Hz,2H) 1.33-1.44 (m, 1H) 1.50-2.12 (m, 11H) 2.22-2.52 (m, 2H) 2.61-2.75 (m,1H) 2.75-2.94 (m, 3H) 3.94-4.09 (m, 0.5H) 4.15 (br. s., 0.5H) 4.35 (d,J=13.28 Hz, 0.5H) 4.42-4.53 (m, 0.5H) 7.21-7.28 (m, 2H) 7.80 (d, J=8.20Hz, 2H); HRMS m/z calcd for C₂₁H₃₀N₃O₂ 356.23325 [M+H]⁺. found356.23294.

Example 174-(trans-2-((S)-4-cyclobutyl-3-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,diastereomeric mixture

Intermediate 14 (300 mg, 1.46 mmol) was dissolved in DMF (15 mL). DIPEA(1.277 mL, 7.31 mmol) was added, followed by HOBT (296 mg, 2.19 mmol),EDC (420 mg, 2.19 mmol) and Intermediate 8 (399 mg, 1.75 mmol). Thereaction mixture was stirred at rt overnight. The reaction mixture wasconcentrated under reduced pressure, redissolved in DCM, washed withsat. NaHCO₃, dried over MgSO₄, filtered and concentrated under reducedpressure. The crude material was purified on preparative HPLC MS usingthe long high pH shallow gradient method (Mobile phase: 5-95% B; A: H₂Owith 10 mM NH₄CO₃ and 0.375% NH₄OH v/v, B: CH₃CN, 25 min. run) onXBridge Prep C18 OBD, 30×150 mm, 5μ, Waters reverse phase column.Fractions were combined and lyophilized to provide 338 mg title compound(67.6%) as a solid (diastereomeric mixture). ¹H NMR (400 MHz, CD₃OD) δppm 0.93 (d, J=6.25 Hz, 1H) 0.98-1.05 (m, 2H) 1.33-1.43 (m, 1H)1.52-1.76 (m, 3H) 1.85-2.14 (m, 4H) 2.17-2.36 (m, 2H) 2.37-2.50 (m, 1H)2.50-2.79 (m, 2H) 3.02-3.15 (m, 1H) 3.25 (ddd, J=13.48, 7.03, 6.84 Hz,1H) 3.52-3.77 (m, 3H) 7.26 (d, J=8.20 Hz, 2H) 7.80 (d, J=7.81 Hz, 2H);HRMS m/z calcd for C₂₀H₂₈N₃O₂ 342.21760 [M+H]⁺. found 342.21790.

Example 184-((trans)-2-((S)-4-cyclobutyl-3-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 1

Example 17 (310.4 mg, 0.91 mmol) (diastereomeric mixture) was separatedon a MettlerToledo Minigram Supercritical Fluid Chromatographyinstrument using the following conditions: ChiralPak AD-H, 10×250 mm, 5μm particle size, 10.0 mL/min, mobile phase: 40% EtOH with 0.1% DMEA,supercritical CO₂, regulator set to 100 Bar, column temperature set to35° C., UV 215 nm, providing 83.2 mg isomer 1 (26.8%) and 132.1 mgisomer 2 (42.6%) as solids. The product was analyzed on chiral SFC (UVdetection) using isocratic method (mobile phase: 55% EtOH with 0.1%DMEA, supercritical CO₂) on Chiral Pak AD, 4.6×250 mm, 20 μm particlesize, giving an enantiomeric purity of 99%, R_(t) 1.92 min (isomer 1)and 2.85 min (isomer 2). Isomer 1: ¹H NMR (400 MHz, CD₃OD) δ ppm0.93-1.07 (m, 3H) 1.29-1.44 (m, 1H) 1.51-1.64 (m, 1H) 1.64-1.75 (m, 2H)1.90 (quin, J=9.77 Hz, 1H) 1.95-2.14 (m, 3H) 2.14-2.37 (m, 2H) 2.40-2.81(m, 3H) 3.00-3.16 (m, 1H) 3.23 (dd, J=13.09, 7.23 Hz, 0.5H) 3.45 (dd,J=13.28, 6.64 Hz, 0.5H) 3.53-3.63 (m, 1H) 3.63-3.90 (m, 2H) 7.25 (d,J=8.20 Hz, 2H) 7.80 (d, J=8.20 Hz, 2H); HRMS m/z calcd for C₂₀H₂₈N₃O₂342.21760 [M+H]⁺. found 342.21771; [α]_(D)+181.6° (c 3.03, MeOH).

Example 194-((trans)-2-((S)-4-cyclobutyl-3-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 2

This isomer was isolated in accordance with the chiral separationdescribed in Example 18 and treated as described therein. The productwas analyzed on chiral SFC (UV detection) using isocratic method (mobilephase: 55% EtOH with 0.1% DMEA, supercritical CO₂) on ChiralPak AD,4.6×250 mm, 20 μm particle size, giving an enantiomeric purity of 99%,R_(t) 1.92 min (isomer 1) and 2.85 min (isomer 2). Isomer 2: ¹H NMR (400MHz, CD₃OD) δ ppm 0.89-1.05 (m, 3H) 1.31-1.44 (m, 1H) 1.55-1.65 (m, 1H)1.65-1.74 (m, 2H) 1.83-1.96 (m, 1H) 1.96-2.04 (m, 2H) 2.04-2.14 (m, 1H)2.15-2.35 (m, 2H) 2.36-2.48 (m, 1H) 2.51-2.77 (m, 2H) 3.01-3.14 (m, 1H)3.25 (dd, J=13.09, 7.23 Hz, 0.5H) 3.47 (dd, J=13.48, 6.05 Hz, 0.5H) 3.55(ddd, J=12.99, 7.91, 3.32 Hz, 0.5H) 3.59-3.67 (m, 0.5H) 3.68-3.80 (m,2H) 7.25 (dd, J=8.20, 1.95 Hz, 2H) 7.80 (d, J=8.20 Hz, 2H); HRMS m/zcalcd for C₂₀H₂₈N₃O₂ 342.21760 [M+H]⁺. found 342.21787; [α]_(D)−190.0°(c 2.69, MeOH).

Example 204-(trans-2-((R)-4-cyclobutyl-3-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,diastereomeric mixture

Intermediate 14 (300 mg, 1.46 mmol) was dissolved in DMF (15 mL). DIPEA(1.277 mL, 7.31 mmol) was added, followed by HOBT (296 mg, 2.19 mmol),EDC (420 mg, 2.19 mmol) and Intermediate 5 (399 mg, 1.75 mmol). Thereaction mixture was stirred at rt overnight. The reaction mixture wasconcentrated under reduced pressure, redissolved in DCM, washed withsat. NaHCO₃, dried over MgSO₄, filtered and concentrated under reducedpressure. The crude material was purified on preparative HPLC MS usingthe long high pH shallow gradient method (Mobile phase: 5-95% B; A: H₂Owith 10 mM NH₄CO₃ and 0.375% NH₄OH v/v, B: CH₃CN, 25 min run) on XBridgePrep C18 OBD, 30×150 mm, 5μ, Waters reverse phase column. Fractions werecombined and lyophilized to provide 360 mg (72.0%) as a solid(diastereomeric mixture). ¹H NMR (400 MHz, CD₃OD) δ ppm 0.93 (d, J=6.64Hz, 1H) 1.02 (d, J=6.25 Hz, 2H) 1.33-1.43 (m, 1H) 1.52-1.75 (m, 3H)1.85-2.15 (m, 4H) 2.16-2.36 (m, 2H) 2.36-2.50 (m, 1H) 2.50-2.78 (m, 2H)3.01-3.16 (m, 1H) 3.19-3.29 (m, 1H) 3.41-3.87 (m, 3H) 7.26 (d, J=8.20Hz, 2H) 7.80 (d, J=7.81 Hz, 2H); HRMS m/z calcd for C₂₀H₂₈N₃O₂ 342.21760[M+H]⁺. found 342.21779.

Example 214-((trans)-2-((R)-4-cyclobutyl-3-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 1

Example 20 (317.7 mg, 0.93 mmol) (diastereomeric mixture) was separatedon a MettlerToledo Minigram Supercritical Fluid Chromatographyinstrument using the following conditions: ChiralPak AD-H, 10×250 mm, 5μm particle size, 10.0 mL/min, mobile phase: 40% EtOH with 0.1% DMEA,supercritical CO₂, regulator set to 100 Bar, column temperature set to35° C., UV 215 nm, providing 133.3 mg isomer 1 (41.9%) and 128.9 mgisomer 2 (40.6%) as solids. The product was analyzed on chiral SFC (UVdetection) using isocratic method (mobile phase: 55% EtOH with 0.1%DMEA, supercritical CO₂) on Chiral Pak AD, 4.6×250 mm, 20 μm particlesize, giving an enantiomeric purity of 99%, R_(t) 1.97 min (isomer 1)and 2.53 min (isomer 2). Isomer 1: ¹H NMR (400 MHz, CD₃OD) δ ppm0.87-1.07 (m, 3H) 1.31-1.42 (m, 1H) 1.54-1.75 (m, 3H) 1.83-2.04 (m, 3H)2.04-2.14 (m, 1H) 2.15-2.35 (m, 2H) 2.35-2.48 (m, 1H) 2.49-2.78 (m, 2H)3.01-3.13 (m, 1H) 3.25 (dd, J=13.09, 7.23 Hz, 0.5H) 3.46 (dd, J=13.28,5.86 Hz, 0.5H) 3.50-3.82 (m, 3H) 7.25 (d, J=6.64 Hz, 2H) 7.80 (d, J=8.20Hz, 2H); HRMS m/z calcd for C₂₀H₂₈N₃O₂ 342.21760 [M+H]⁺. found342.21820; [α]_(D)+183.0° (c 3.99, MeOH).

Example 224-((trans)-2-((R)-4-cyclobutyl-3-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 2

This isomer was isolated in accordance with the chiral separationdescribed in Example 21 and treated as described therein. The productwas analyzed on chiral SFC (UV detection) using isocratic method (mobilephase: 55% EtOH with 0.1% DMEA, supercritical CO₂) on ChiralPak AD,4.6×250 mm, 20 μm particle size, giving an enantiomeric purity of 99%,R_(t) 1.97 min (isomer 1) and 2.53 min (isomer 2). Isomer 2: ¹H NMR (400MHz, CD₃OD) δ ppm 0.95-1.06 (m, 3H) 1.33-1.44 (m, 1H) 1.51-1.63 (m, 1H)1.63-1.76 (m, 2H) 1.91 (quin, J=10.60 Hz, 1H) 1.96-2.15 (m, 3H)2.16-2.36 (m, 2H) 2.40-2.50 (m, 1H) 2.50-2.77 (m, 1H) 3.01-3.14 (m, 1H)3.23 (dd, J=13.09, 7.23 Hz, 1H) 3.39-3.49 (m, 1H) 3.52-3.63 (m, 1H)3.63-3.76 (m, 1H) 3.82 (ddd, J=12.79, 5.76, 2.93 Hz, 1H) 7.25 (d, J=8.20Hz, 2H) 7.80 (d, J=8.59 Hz, 2H); HRMS m/z calcd for C₂₀H₂₈N₃O₂ 342.21760[M+H]⁺. found 342.21757; [α]_(D)−190.5° (c 3.25, MeOH).

Example 234-(trans-2-(4-cyclobutyl-2,2-dimethylpiperazine-1-carbonyl)cyclopropyl)benzamide,enantiomeric mixture

Intermediate 24 (295 mg, 0.98 mmol) was dissolved in DCE (10 mL). TEA(1.366 mL, 9.80 mmol) was added, followed by cyclobutanone (137 mg, 1.96mmol) and sodium triacetoxyborohydride (312 mg, 1.47 mmol). The reactionmixture was stirred for 5 days at rt, washed with sat NaHCO₃, dried overMgSO₄, filtered and concentrated under reduced pressure. The crudematerial was purified on preparative HPLC MS using the short high pHshallow gradient method (Mobile phase: 20-40% B; A: H₂O with 10 mMNH₄CO₃ and 0.375% NH₄OH v/v, B: CH₃CN, 10 min run) on XBridge Prep C18OBD, 30×50 mm, 5 μm, Waters reverse phase column, providing 101 mg titlecompound (29.0%) as a solid (enantiomeric mixture). ¹H NMR (400 MHz,CD₃OD) δ ppm 1.30 (ddd, J=8.40, 6.05, 4.30 Hz, 1H) 1.38-1.47 (m, 6H)1.49-1.57 (m, 1H) 1.66-1.79 (m, 2H) 1.90 (quin, J=9.57 Hz, 2H) 1.98-2.09(m, 2H) 2.10-2.27 (m, 3H) 2.29-2.51 (m, 3H) 2.76 (br. s., 1H) 3.54-3.71(m, 2H) 7.24 (d, J=8.59 Hz, 2H) 7.79 (d, J=8.59 Hz, 2H); HRMS m/z calcdfor C₂₁H₃₀N₃O₂ 356.23325 [M+H]⁺. found 356.23291.

Example 244-(trans-2-(4-cyclobutyl-3,3-dimethylpiperazine-1-carbonyl)cyclopropyl)benzamide,enantiomeric mixture

Intermediate 14 (282 mg, 1.38 mmol) was dissolved in DMF (15 mL). DIPEA(1.201 mL, 6.88 mmol) was added, followed by HOBT (279 mg, 2.06 mmol),EDC (395 mg, 2.06 mmol) and Intermediate 2 (278 mg, 1.65 mmol). Thereaction mixture was stirred at rt for 2 h and concentrated underreduced pressure. The residue was redissolved in DCM, washed with satNaHCO₃, dried over MgSO₄, filtered and concentrated under reducedpressure to give 632 mg of crude as an orange oil. The crude materialwas purified on preparative HPLC UV using the long high pH shallowgradient method (Mobile phase: 20-40% B; A: H₂O with 10 mM NH₄CO₃ and0.375% NH₄OH v/v, B: CH₃CN, 30 min run) on XBridge Prep C18 OBD, 50×250mm, 10μ, Waters reverse phase column, providing 151 mg title compound(30.9%) as a solid (enantiomeric mixture). ¹H NMR (400 MHz, CD₃OD) δ ppm1.01 (s, 2H) 1.08 (s, 4H) 1.34-1.43 (m, 1H) 1.55-1.70 (m, 4H) 1.96-2.12(m, 5H) 2.25-2.37 (m, 1H) 2.40-2.48 (m, 1H) 2.61 (br. s., 2H) 3.45 (br.s., 2H) 3.75 (br. s., 1H) 7.26 (dd, J=8.20, 5.08 Hz, 2H) 7.80 (dd,J=8.40, 2.93 Hz, 2H); HRMS m/z calcd for C₂₁H₃₀N₃O₂ 356.23325 [M+H]⁺.found 356.23286.

Example 254-(trans-2-(4-cyclobutyl-3,3-dimethylpiperazine-1-carbonyl)cyclopropyl)benzamide,enantiomer 1

Example 24 (124 mg, 0.35 mmol) (enantiomeric mixture) was separated on aMettlerToledo Minigram Supercritical Fluid Chromatography instrumentusing the following conditions: ChiralPak AD-H, 10×250 mm, 5 μm particlesize, 10.0 mL/min, mobile phase: 55% MeOH with 0.1% DMEA, supercriticalCO₂, regulator set to 100 Bar, column temperature set to 35° C., UV 215nm, providing 49.1 mg enantiomer 1 (79%) and 48.3 mg enantiomer 2 (78%)as solids. The product was analyzed on chiral SFC (UV detection) usingisocratic method (mobile phase: 55% MeOH with 0.1% DMEA, supercriticalCO₂) on ChiralPak AD-H, 10×250 mm, 5 μm particle size, giving anenantiomeric purity of 99%, R_(t) 2.11 min (enantiomer 1) and 3.18 min(enantiomer 2). Enantiomer 1: ¹H NMR (400 MHz, CD₃OD) δ ppm 0.97 (s, 2H)1.05 (s, 4H) 1.34-1.42 (m, 1H) 1.55-1.68 (m, 3H) 1.93-2.11 (m, 4H)2.24-2.37 (m, 1H) 2.39-2.47 (m, 1H) 2.47-2.66 (m, 2H) 3.32-3.47 (m, 3H)3.48-3.58 (m, 0.5H) 3.63-3.81 (m, 1.5H) 7.26 (dd, J=8.20, 5.08 Hz, 2H)7.80 (dd, J=8.40, 3.32 Hz, 2H); HRMS m/z calcd for C₂₁H₃₀N₃O₂356.2333[M+H]⁺. found 356.2332; [α]_(D)+193° (c 0.42, MeOH).

Example 264-(trans-2-(4-cyclobutyl-3,3-dimethylpiperazine-1-carbonyl)cyclopropyl)benzamide,enantiomer 2

This isomer was isolated in accordance with the chiral separationdescribed in Example 25 and treated as described therein. The productwas analyzed on chiral SFC (UV detection) using isocratic method (mobilephase: 55% MeOH with 0.1% DMEA, supercritical CO₂) on ChiralPak AD-H,10×250 mm, 5 μm particle size, giving an enantiomeric purity of 99%,R_(t) 2.11 min (enantiomer 1) and 3.18 min (enantiomer 2). Enantiomer 2:¹H NMR (400 MHz, CD₃OD) δ ppm 0.97 (s, 2H) 1.05 (s, 4H) 1.38 (dddd,J=8.40, 6.15, 5.96, 4.49 Hz, 1H) 1.55-1.68 (m, 3H) 1.93-2.11 (m, 4H)2.24-2.37 (m, 1H) 2.40-2.47 (m, 1H) 2.47-2.65 (m, 2H) 3.32-3.47 (m, 3H)3.47-3.58 (m, 1H) 3.63-3.80 (m, 1H) 7.26 (dd, J=8.40, 5.27 Hz, 2H) 7.80(dd, J=8.59, 3.52 Hz, 2H); HRMS m/z calcd for C₂₁H₃₀N₃O₂ 356.2333[M+H]⁺. found 356.2331; [α]_(D)−195° (c 0.49, MeOH).

Example 273-(trans-2-((R)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,diastereomeric mixture

Intermediate 30 (101 mg, 0.35 mmol) was dissolved in DCE (3.5 mL). TEA(0.098 mL, 0.70 mmol) was added, followed by cyclobutanone (49.1 mg,0.70 mmol) and sodium triacetoxyborohydride (111 mg, 0.53 mmol). Thereaction mixture was stirred overnight, washed with sat. NaHCO₃, driedover MgSO₄, filtered and concentrated under reduced pressure. The crudematerial was purified on preparative HPLC MS using the short high pHshallow gradient method (Mobile phase: 20-40% B; A: H₂O with 10 mMNH₄CO₃ and 0.375% NH₄OH v/v, B: CH₃CN, 10 min run) on XBridge Prep C18OBD, 30×50 mm, 5 μm, Waters reverse phase column, providing 73.7 mgtitle compound (61.7%) as a solid (diastereomeric mixture). ¹H NMR (400MHz, CD₃OD) δ ppm 1.28 (br. s., 4H) 1.58 (dt, J=9.08, 4.64 Hz, 1H)1.64-2.11 (m, 8H) 2.27 (dt, J=8.69, 4.44 Hz, 1H) 2.44 (br. s., 1H)2.62-2.78 (m, 2H) 2.85 (d, J=9.37 Hz, 1H) 2.97 (br. s., 1H) 4.04 (br.s., 0.5H) 4.29 (br. s., 0.5H) 4.49 (br. s., 0.5H) 4.67 (br. s., 0.5H)7.33-7.44 (m, 2H) 7.63 (s, 1H) 7.70 (t, J=4.30 Hz, 1H); HRMS m/z calcdfor C₂₀H₂₈N₃O₂ 342.21760 [M+H]⁺. found 342.21788.

Example 283-((trans)-2-((R)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 1

Example 27 (50.9 mg, 0.15 mmol) (diastereomeric mixture) was separatedon a MettlerToledo Minigram Supercritical Fluid Chromatographyinstrument using the following conditions: ChiralPak AD-H, 10×250 mm, 5μm particle size, 10.0 mL/min, mobile phase: 40% MeOH with 0.1% DMEA,supercritical CO₂, regulator set to 100 Bar, column temperature set to35° C., UV 215 nm, providing 23.9 mg isomer 1 (47.0%) and 23.2 mg isomer2 (45.7%) as solids. The product was analyzed on chiral SFC (UVdetection) using isocratic method (mobile phase: 40% iPrOH with 0.1%DMEA, supercritical CO₂) on ChiralPak AD, 4.6×250 mm, 20 μm particlesize, giving an enantiomeric purity of 99%, R_(t) 2.78 min (isomer 1)and 4.02 min (isomer 2). Isomer 1: ¹H NMR (400 MHz, CD₃OD) δ ppm 1.27(br. s., 1H) 1.39 (br. s., 3H) 1.53-1.64 (m, 1H) 1.64-2.14 (m, 8H) 2.27(dd, J=8.20, 4.69 Hz, 1H) 2.36-2.52 (m, 1H) 2.62-2.79 (m, 2H) 2.85 (d,J=10.55 Hz, 1H) 2.90-3.06 (m, 0.5H) 3.34-3.48 (m, 0.5H) 4.06 (d, J=14.06Hz, 0.5H) 4.32 (d, J=14.84 Hz, 0.5H) 4.41-4.48 (m, 0.5H) 4.57-4.75 (m,0.5H) 7.38 (d, J=4.30 Hz, 2H) 7.63 (s, 1H) 7.70 (t, J=3.52 Hz, 1H); HRMSm/z calcd for C₂₀H₂₈N₃O₂ 342.21760 [M+H]⁺. found 342.21776;[α]_(D)+127.2° (c 0.79, MeOH).

Example 293-((trans)-2-((R)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 2

This isomer was isolated in accordance with the chiral separationdescribed in Example 28 and treated as described therein. The productwas analyzed on chiral SFC (UV detection) using isocratic method (mobilephase: 40% iPrOH with 0.1% DMEA, supercritical CO₂) on ChiralPak AD,4.6×250 mm, 20 μm particle size, giving an enantiomeric purity of 99%,R_(t) 2.78 min (isomer 1) and 4.02 min (isomer 2). Isomer 2: ¹H NMR (400MHz, CD₃OD) δ ppm 1.28 (d, J=3.12 Hz, 3H) 1.38 (br. s., 1H) 1.49-1.65(m, 1H) 1.65-2.16 (m, 8H) 2.27 (br. s., 1H) 2.43 (br. s., 1H) 2.62-2.78(m, 2H) 2.84 (br. s., 1H) 2.91-3.03 (m, 0.5H) 3.37-3.49 (m, 0.5H) 4.02(d, J=13.28 Hz, 0.5H) 4.29 (d, J=12.50 Hz, 0.5H) 4.47 (br. s., 0.5H)4.68 (br. s., 0.5H) 7.38 (d, J=4.30 Hz, 2H) 7.63 (s, 1H) 7.70 (ddd,J=4.98, 3.61, 1.56 Hz, 1H); HRMS m/z calcd for C₂₀H₂₈N₃O₂ 342.21760[M+H]⁺. found 342.21766; [α]_(D)−191.9° (c 0.64, MeOH).

Example 303-(trans-2-((S)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,diastereomeric mixture

Intermediate 31 (98 mg, 0.34 mmol) was dissolved in DCE (3.5 mL). TEA(0.095 mL, 0.68 mmol) was added, followed by cyclobutanone (47.7 mg,0.68 mmol) and sodium triacetoxyborohydride (108 mg, 0.51 mmol). Thereaction mixture was stirred overnight, washed with sat. NaHCO₃, driedover MgSO₄, filtered and concentrated under reduced pressure to give78.2 mg of crude as an orange oil. The crude material was purified onpreparative HPLC MS using the short high pH shallow gradient method(Mobile phase: 20-40% B; A: H₂O with 10 mM NH₄CO₃ and 0.375% NH₄OH v/v,B: CH₃CN, 10 min run) on XBridge Prep C18 OBD, 30×50 mm, 5 μm, Watersreverse phase column, providing 63.6 mg title compound (54.8%) as asolid (diastereomeric mixture). ¹H NMR (400 MHz, CD₃OD) δ ppm 1.27 (br.s., 4H) 1.58 (ddd, J=9.18, 4.88, 4.69 Hz, 1H) 1.65-2.12 (m, 8H)2.18-2.34 (m, 1H) 2.45 (br. s., 1H) 2.61-2.78 (m, 2H) 2.85 (d, J=12.89Hz, 1H) 2.97 (t, J=12.89 Hz, 1H) 4.04 (br. s., 0.5H) 4.30 (br. s., 0.5H)4.46 (br. s., 0.5H) 4.67 (br. s., 0.5H) 7.30-7.45 (m, 2H) 7.63 (s, 1H)7.66-7.76 (m, 1H); HRMS m/z calcd for C₂₀H₂₈N₃O₂ 342.21760 [M+H]⁺. found342.21769.

Example 313-((trans)-2-((S)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 1

Example 30 (39.9 mg, 0.12 mmol)(diastereomeric mixture) was separated ona MettlerToledo Minigram Supercritical Fluid Chromatography instrumentusing the following conditions: ChiralPak AS-H, 10×250 mm, 5 μm particlesize, 10.0 mL/min, mobile phase: 45% iPrOH with 0.1% DMEA, supercriticalCO₂, regulator set to 100 Bar, column temperature set to 35° C., UV 215nm, providing 17.0 mg isomer 1 (42.7%) and 14.1 mg isomer 2 (35.3%) assolids. The product was analyzed on chiral SFC (UV detection) usingisocratic method (mobile phase: 45% iPrOH with 0.1% DMEA, supercriticalCO₂) on ChiralPak AS-H, 10×250 mm, 5 μm particle size, giving anenantiomeric purity of 99%, R_(t) 3.55 min (isomer 1) and 5.58 min(isomer 2). Isomer 1: ¹H NMR (400 MHz, CD₃OD) δ ppm 1.28 (d, J=2.34 Hz,3H) 1.38 (br. s., 1H) 1.65 (br. s., 1H) 1.66-2.12 (m, 8H) 2.27 (br. s.,1H) 2.43 (br. s., 1H) 2.63-2.78 (m, 2H) 2.84 (br. s., 1H) 2.91-3.10 (m,0.5H) 3.37-3.53 (m, 0.5H) 3.95-4.09 (m, 0.5H) 4.19-4.35 (m, 0.5H) 4.47(br. s., 0.5H) 4.68 (br. s., 0.5H) 7.38 (d, J=4.30 Hz, 2H) 7.63 (br. s.,1H) 7.66-7.74 (m, 1H); HRMS m/z calcd for C₂₀H₂₈N₃O₂ 342.21760 [M+H]⁺.found 342.21726; [α]_(D)+269.1° (c 0.21, MeOH).

Example 323-((trans)-2-((S)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 2

This isomer was isolated in accordance with the chiral separationdescribed in Example 31 and treated as described therein. The productwas analyzed on chiral SFC (UV detection) using isocratic method (mobilephase: 45% iPrOH with 0.1% DMEA, supercritical CO₂) on ChiralPak AS-H,10×250 mm, 5 μm particle size, giving an enantiomeric purity of 99%,R_(t) 3.55 min (isomer 1) and 5.58 min (isomer 2). Isomer 2: ¹H NMR (400MHz, CD₃OD) δ ppm 1.27 (br. s., 1H) 1.39 (br. s., 3H) 1.50-1.64 (m, 1H)1.64-2.15 (m, 8H) 2.18-2.35 (m, 1H) 2.44 (br. s., 1H) 2.61-2.77 (m, 2H)2.85 (d, J=11.33 Hz, 1H) 2.90-3.06 (m, 0.5H) 3.35-3.47 (m, 0.5H) 4.06(d, J=12.89 Hz, 0.5H) 4.32 (d, J=12.50 Hz, 0.5H) 4.36-4.51 (m, 0.5H)4.66 (br. s., 0.5H) 7.38 (d, J=4.69 Hz, 2H) 7.63 (s, 1H) 7.68-7.77 (m,1H); HRMS m/z calcd for C₂₀H₂₈N₃O₂ 342.21760 [M+H]⁺. found 342.21762;[α]_(D)−114.9° (c 0.56, MeOH).

Example 333-(trans-2-((S)-4-cyclobutyl-3-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,diastereomeric mixture

Oxalyl chloride (0.256 mL, 2.92 mmol) was slowly added to a solution ofintermediate 27 (200 mg, 0.97 mmol) in DCM (3.0 mL) at 0° C. under anitrogen atmosphere. The solution was stirred for 3 h while warming tort. The solvent was concentrated under reduced pressure and the residuewas redissolved in DCM (1.0 mL). The resulting solution was addeddropwise to a solution of intermediate 8 and DIPEA (0.851 mL, 4.87 mmol)in DCM (3.0 mL) at 0° C. under a nitrogen atmosphere. The reactionmixture was stirred overnight and the solvent was evaporated to give thecrude product as a dark orange gummy solid. The crude material waspurified on preparative HPLC UV using the long high pH shallow gradientmethod (Mobile phase: 30-50% B; A: H₂O with 10 mM NH₄CO₃ and 0.375%NH₄OH v/v, B: CH₃CN, 25 min run) on XBridge Prep C18 OBD, 30×150 mm, 5μ,Waters reverse phase column, providing 69.2 mg title compound (20.79%)as a solid (diastereomeric mixture). ¹H NMR (400 MHz, CD₃OD) δ ppm0.91-1.07 (m, 3H) 1.33-1.45 (m, 1H) 1.50-1.63 (m, 1H) 1.63-1.76 (m, 2H)1.85-2.15 (m, 4H) 2.17-2.35 (m, 2H) 2.37-2.51 (m, 1H) 2.52-2.80 (m, 2H)3.01-3.17 (m, 1H) 3.19-3.53 (m, 1H) 3.53-3.90 (m, 3H) 7.33-7.44 (m, 2H)7.63 (s, 1H) 7.66-7.76 (m, 1H); HRMS m/z calcd for C₂₀H₂₈N₃O₂ 342.21760[M+H]⁺. found 342.21697.

Example 343-(trans-2-((R)-4-cyclobutyl-3-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,diastereomeric mixture

Oxalyl chloride (0.256 mL, 2.92 mmol) was slowly added to a solution ofintermediate 27 (200 mg, 0.97 mmol) in DCM (3.0 mL) at 0° C. under anitrogen atmosphere. The solution was stirred for 3 h while warming tort. The solvent was concentrated under reduced pressure and the residuewas redissolved in DCM (1.0 mL). The resulting solution was addeddropwise to a solution of intermediate 5 (221 mg, 0.97 mmol) and DIPEA(0.851 mL, 4.87 mmol) in DCM (3.0 mL) at 0° C. under a nitrogenatmosphere. The reaction mixture was stirred overnight and the solventwas evaporated to give the crude product as a dark yellow gummy solid.The crude material was purified on preparative HPLC UV using the longhigh pH shallow gradient method (Mobile phase: 30-50% B; A: H₂O with 10mM NH₄CO₃ and 0.375% NH₄OH v/v, B: CH₃CN, 25 min run) on XBridge PrepC18 OBD, 30×150 mm, 5μ, Waters reverse phase column, providing 74.5 mgtitle compound (22.39%) as a solid (diastereomeric mixture). ¹H NMR (400MHz, CD₃OD) δ ppm 0.90-1.08 (m, 3H) 1.33-1.45 (m, 1H) 1.50-1.63 (m, 1H)1.63-1.77 (m, 2H) 1.85-2.15 (m, 4H) 2.17-2.35 (m, 2H) 2.38-2.51 (m, 1H)2.51-2.80 (m, 2H) 3.02-3.16 (m, 1H) 3.20-3.54 (m, 1H) 3.53-3.91 (m, 3H)7.33-7.42 (m, 2H) 7.63 (s, 1H) 7.66-7.74 (m, 1H); HRMS m/z calcd forC₂₀H₂₈N₃O₂ 342.21760 [M+H]⁺. found 342.21964.

Example 35 First Method4-{(1S,2S)-2-[((R)-4-Cyclobutyl-2-methylpiperazin-1-yl)carbonyl]-cyclopropyl}-benzamide

Intermediate 37 (389 g, 1.90 moles) was mixed in 2-MeTHF (6.7 L) att_(jacket)=25° C. 1,1′-Carbonyldiimidazole (412 g, 2.09 moles, 82.1%w/w) was added in 1 portion. The reaction slurry was heated tot_(jacket)=55° C. The gas evolution decreased after approximately 1 h.The reaction slurry was heated to t_(jacket)=85° C. for 3 h and thencooled to t_(jacket)=50° C. Intermediate 32 (490 g, 2.08 moles, 96.3%w/w) and TEA (290 mL, 2.09 moles) were added to the reaction slurry.2-MeTHF (2 L) was used for rinsing. The reaction slurry was heated att_(jacket)=70° C. for 4 h. Analyzing a sample on HPLC indicated fullconversion at this point. The reaction slurry was cooled tot_(jacket)=20° C. 1M Na₂CO₃ in brine (2 L) was added and the temperaturewas adjusted to t_(jacket)=40° C. The aq. phase was separated off andthe organic phase washed with brine (2 L). The organic phase wasextracted with 5% H₃PO₄ in H₂O (1.5 L×4) at t_(jacket)=20° C. Thecombined aq. phases were washed with DCM (1 L). Very slow phaseseparation occurred. The combined aq. phases were basified to pH>11 with5M NaOH and extracted with DCM (1.2 L×2). The combined organic phaseswere concentrated under vacuum to dryness. The residual oil wasdissolved in acetonitrile (1.2 L) at t_(jacket)=50° C. Seed was addedand the solution was stirred for 30 min. at t_(jacket)=40° C. Themixture was cooled to t_(jacket)=5° C. over 6 h and the product wasfiltered off. Drying under vacuum at 40° C. gave 372 g Example 35 (1.04moles, 100% w/w) as a first crop. The mother liquid was recrystallizedfrom acetonitrile and a second crop could be isolated of Example 35 (77g, 0.21 moles, 98.7% w/w). Example 35 was isolated in a total yield of66%. Example 35 corresponds to Example 8 (isomer 1). ¹H-NMR (DMSO-d₆): δ7.91 (br s, 1H), 7.78 (d, J=8.4 Hz, 2H), 7.30 (br s, 1H), 7.25 (d, J=8.0Hz, 2H), 4.54 and 4.36 (br s, 1H), 4.17 and 4.01 (d, J=12.2 Hz, 1H),3.20 and 2.80 (t, J=11.9 Hz, 1H), 2.74 (d, J=11.4 Hz, 1H), 2.67-2.55 (m,2H), 2.33 (br s, 2H), 1.99-1.88 (m, 2H), 1.88-1.53 (m, 6H), 1.48-1.37(m, 1H), 1.27 (br s, 3H), 1.12 (br s, 1H); LC-MS (ES): m/z 342 (M+1).R_(t) 1.68 min with the analytical method (mobile phase: 5-90% B; A: H₂Owith 0.1% formic acid, B: CH₃CN, 8.6 min run) on Xbridge C18, 3.0×50 mm,2.5 μm particle size.

Example 35 Second Method4-{(1S,2S)-2-[((R)-4-Cyclobutyl-2-methylpiperazin-1-yl)carbonyl]-cyclopropyl}-benzamide

N₂ was bubbled into Intermediate 39 (6.09 g, 18.83 mmol) in EtOH (125mL) and H₂O (30 mL). To this was added Hydrido(dimethylphosphinousacid-kP)[hydrogen bis(dimethylphosphnito-kP]platinum (II) (0.050 g, 0.12mmol). The reaction was heated at reflux for 20 h. The reaction washeated for a further 24 h, concentrated to dryness and partitionedbetween EtOAc and H₂O. The aq. phase was extracted 3× with EtOAc, thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated. The crude material was purified by flashchromatography on silica gel, eluting with a gradient of CH₂Cl₂ andMeOH, 2-10% with a plateau at 4% until elution of visible dark bandfollowed by a second purification with a gradient of acetone/heptane30-100% to afford 3.65 g Example 35 (56.8% yield) as a solid. ¹H NMR(400 MHz, CD₃OD) δ ppm 1.24 (br. s., 1H) 1.36 (br. s., 3H) 1.52-1.60 (m,1H) 1.63-1.74 (m, 3H) 1.74-1.84 (m, 1H) 1.84-1.95 (m, 2H) 1.95-2.05 (m,2H) 2.24 (br. s., 1H) 2.40 (br. s., 1H) 2.60-2.72 (m, 2H) 2.82 (d,J=12.50 Hz, 1H) 2.94 and 3.36 (t, J=12.11 Hz, 1H) 4.01 and 4.28 (d,J=13.28 Hz, 1H) 4.35 and 4.62 (br. s., 1H) 7.22 (d, J=8.20 Hz, 2H) 7.77(d, J=8.59 Hz, 2H). The product was analyzed on analytical HPLC MS usingthe Zorbax gradient method (mobile phase: 5-95% B; A: H₂O with 0.05%TFA, B: CH₃CN, 4.5 min run) on Zorbax SB C18, 4.6×30 mm, 1.8 μm particlesize. MS m/z 342.3 [M+H]⁺ (ESI), R_(t)=0.584 min. The product wasanalyzed on chiral SFC (UV detection) using isocratic method (mobilephase: 55% EtOH with 0.1% DMEA, supercritical CO₂) on ChiralPak AD-H,10×250 mm, 5 μm particle size, giving an enantiomeric purity of >99%,R_(t) 1.98 min. Example 35 corresponds to Example 8 (isomer 1). HRMS m/zcalcd for C₂₀H₂₇N₃O₂ 342.2176 [M+H]⁺. found 342.2176.

Example 35 Crystalline Form I4-{(1S,2S)-2-[((R)-4-Cyclobutyl-2-methylpiperazin-1-yl)carbonyl]-cyclopropyl}-benzamide,Crystalline Form I

In a first means of preparing Crystalline Form I, 20 mg of an amorphousform of4-{(1S,2S)-2-[((R)-4-Cyclobutyl-2-methylpiperazin-1-yl)carbonyl]-cyclopropyl}-benzamidewas added to a vessel. To the vessel, 100 μl of EtOAc was added toobtain a suspension. The resulting slurry was stirred at ambienttemperature for 3 days. Solid material was then isolated and dried inair.

In a second means of preparing Crystalline Form I, 20 mg of an amorphousform of4-{(1S,2S)-2-[((R)-4-Cyclobutyl-2-methylpiperazin-1-yl)carbonyl]-cyclopropyl}-benzamidewas added to a vessel. To the vessel, 100 μl of acetonitrile was addedto obtain a suspension. The resulting slurry was stirred at ambienttemperature for 3 days. Solid material was then isolated and dried inair.

The solid material obtained via at least one of the processes set forthabove was analyzed by XRPD. Selected peaks are provided in Table 1. Arepresentative XRPD pattern is shown in FIG. 1. The XRPD patternconfirmed the solid material to be Crystalline Form I.

TABLE 2 Selected XRPD Peaks of Crystalline Form I Relative Peak °20Intensity (%) 1 4.6 51.7 2 7.6 43.2 3 11.8 30.8 4 14.1 20.9 5 15.3 48.76 15.5 100.0 7 15.9 36.9 8 17.4 76.8 9 18.9 50.7 10 22.2 33.8

INTERMEDIATES Intermediate 1 tert-butyl4-cyclobutyl-3,3-dimethylpiperazine-1-carboxylate

Tert-butyl 3,3-dimethylpiperazine-1-carboxylate (413 mg, 1.65 mmol) wasdissolved in DCE (15 mL). TEA (1.148 mL, 8.23 mmol) was added, followedby cyclobutanone (231 mg, 3.29 mmol) and sodium triacetoxyborohydride(524 mg, 2.47 mmol). The reaction mixture was stirred for 5 h and a fewdrops of acetic acid were added. The reaction mixture was heated at 40°C. for 4 days, cooled to rt, washed with sat NaHCO₃, dried over MgSO₄,filtered and concentrated under reduced pressure to give a dark yellowoil. The crude title compound was used in the next step without furtherpurification.

Intermediate 2 1-cyclobutyl-2,2-dimethylpiperazine

Intermediate 1 (0.443 g, 1.65 mmol) was dissolved in DCM (10 mL) and TFA(5.00 mL) was added. The reaction mixture was stirred for 1.5 h, thenwas concentrated under reduced pressure and dried under vacuum. Thecrude title compound was used in the next step without purification.

Intermediate 3 (R)-tert-butyl 3-methylpiperazine-1-carboxylate

(R)-2-methylpiperazine (5.025 g, 50.2 mmol) was dissolved in DCM (100mL). A solution of boc anhydride (5.47 g, 25.1 mmol) in DCM (50 mL) wasadded dropwise at 0° C. The reaction mixture was stirred at rt for 1 h.The solution was filtered and concentrated under reduced pressure. Water(100 mL) was added to the residue, which was filtered again. Thefiltrate was saturated with K₂CO₃ and extracted with Et₂O (3×150 mL).The combined organic layers were dried over anhydrous Na₂SO₄, filteredand concentrated under reduced pressure to provide 5.04 g title compound(50%) as a solid. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.03 (d, J=6.3 Hz, 3H)1.45 (s, 9H) 1.56 (s, 1H) 2.30-2.46 (m, 1H) 2.65-2.72 (m, 1H) 2.74-2.76(m, 2H) 2.93-2.95 (m, 1H) 3.93 (br s, 2H).

Intermediate 4 (R)-tert-butyl4-cyclobutyl-3-methylpiperazine-1-carboxylate

Intermediate 3 (2.63 g, 13.1 mmol) was dissolved in DCE (60 mL).Cyclobutanone (1.38 g, 19.7 mmol) and acetic acid (0.75 mL, 13.1 mmol)were added and the mixture stirred at rt for 30 min. NaBH(OAc)₃ (4.18 g,19.7 mmol) was added portionwise and the mixture was stirred at rtovernight. Sat. Na₂CO₃ (50 mL) was added and the aq. layer was extractedwith DCM (3×75 mL). The combined organic phases were dried over Na₂SO₄,filtered and concentrated under reduced pressure to provide 2.58 g titlecompound (77%) as an oil. 1H NMR (300 MHz, CDCl₃) δ ppm 0.97 (d, J=6.4Hz, 3H) 1.45 (s, 9H) 1.61-1.70 (m, 2H) 1.81-1.91 (m, 1H) 1.93-2.00 (m,2H) 2.03-2.14 (m, 2H) 2.41-2.51 (m, 1H) 2.58-2.65 (m, 1H) 2.94-3.05 (m,1H) 3.06-3.16 (m, 1H) 3.29-3.58 (m, 3H).

Intermediate 5 (R)-1-cyclobutyl-2-methylpiperazine

Intermediate 4 (2.58 g, 10.2 mmol) was dissolved in MeOH (30 mL). 4 MHCl in dioxane (10 mL) was added and the mixture was stirred at rtovernight. Volatiles were evaporated and the residue dissolved with asmall quantity of MeOH. The solution was added dropwise to a largequantity of Et₂O with vigorous stirring. The precipitate was filteredand dried under reduced pressure to provide 2.01 g title compound (87%)as the hydrochloride salt. ¹H NMR (300 MHz, CD₃OD) δ ppm 1.48 (d, J=6.7Hz, 3H) 1.80-1.97 (m, 2H) 2.31-2.46 (m, 3H) 2.58-2.77 (m, 1H) 3.15-3.28(m, 1H) 3.38-3.50 (m, 1H) 3.54-3.81 (m, 5H) 4.00 (q, J=8.3, 16.6 Hz,1H); MS m/z 155.37 [M+H]⁺ (ES+); [α]_(D)−12.95° (c 2.95, MeOH).

Intermediate 6 (S)-tert-butyl 3-methylpiperazine-1-carboxylate

(S)-2-methylpiperazine (5.00 g, 49.9 mmol) was dissolved in DCM (150mL). A solution of boc anhydride (5.47 g, 25.0 mmol) in DCM (50 mL) wasadded dropwise at 0° C. The reaction mixture was stirred at rt for 2 h.The solution was filtered and concentrated under reduced pressure. Water(100 mL) was added to the residue and it was filtered again. Thefiltrate was saturated with K₂CO₃ and extracted with Et₂O (3×150 mL).The combined organic layers were dried over anhydrous Na₂SO₄, filteredand concentrated under reduced pressure to provide 4.92 g title compound(49%) as a solid. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.03 (d, J=6.3 Hz, 3H)1.45 (s, 9H) 1.53 (br. s, 1H) 2.38 (t, J=11.8 Hz, 1H) 2.65-2.72 (m, 1H)2.74-2.76 (m, 2H) 2.92-2.95 (m, 1H) 3.92 (br. s, 2H).

Intermediate 7 (S)-tert-butyl4-cyclobutyl-3-methylpiperazine-1-carboxylate

Intermediate 6 (3.00 g, 15.0 mmol) was dissolved in DCE (65 mL).Cyclobutanone (1.58 g, 22.5 mmol) and acetic acid (0.86 mL, 15.0 mmol)were added and the mixture stirred at rt for 30 min. NaBH(OAc)₃ (4.76 g,22.5 mmol) was added portionwise and the mixture was stirred at rtovernight. Sat. Na₂CO₃ (50 mL) was added and the aq. layer was extractedwith DCM (3×75 mL). The combined organic phases were dried over Na₂SO₄,filtered and concentrated under reduced pressure to provide 3.45 g titlecompound (90%) as an oil. 1H NMR (300 MHz, CDCl₃) δ ppm 1.00 (d, J=6.5Hz, 3H) 1.41 (s, 9H) 1.54-1.73 (m, 2H) 1.89-1.96 (m, 1H) 2.00-2.14 (m,3H) 2.26 (br. s, 1H) 2.65 (br. s, 2H) 2.99-3.10 (m, 1H) 3.20 (br. s, 1H)3.46 (br. s, 3H).

Intermediate 8 (S)-1-cyclobutyl-2-methylpiperazine

Intermediate 7 (3.45 g, 13.6 mmol) was dissolved in MeOH (40 mL). 4 MHCl in dioxane (10 mL) was added and the mixture was stirred at rtovernight. Volatiles were evaporated under reduced pressure and theresidue dissolved with a small quantity of MeOH. The solution was addeddropwise to a large quantity of Et₂O with vigorous stirring. Theprecipitate was filtered and dried under reduced pressure to provide2.32 g title compound (75%) as the hydrochloride salt. ¹H NMR (300 MHz,CD₃OD) δ ppm 1.46-1.50 (m, 3H) 1.81-1.97 (m, 2H) 2.35-2.46 (m, 3H)2.58-2.79 (m, 1H) 3.15-3.28 (m, 1H) 3.39-3.51 (m, 1H) 3.54-3.82 (m, 5H)4.01 (m, 1H); MS m/z 155.42 [M+H]⁺ (ES+); [α]_(D)+23.43° (c 4.0, MeOH).

Intermediate 9 (E)-tert-butyl 3-(4-cyanophenyl)acrylate

A flame dried three-neck round-bottom flask equipped with a magneticstirring bar, a thermometer, an addition funnel and a nitrogen inlet wascharged with NaH (3.96 g, 94.7 mmol) and anhydrous THF (120 mL).Tert-butyl diethylphosphonoacetate (23.2 mL, 94.7 mmol) dissolved inanhydrous THF (20 mL) was added dropwise via the addition funnel over aperiod of 30 min. After the completion of addition, the reaction mixturewas stirred at rt for another 30 min. A solution of 4-cyanobenzaldehyde(11.3 g, 86.1 mmol) dissolved in anhydrous THF (20 mL) was added to thereaction mixture dropwise via the addition funnel over a period of 30min. After the end of the addition, the reaction mixture was stirred atrt for 1 h, then diluted with MTBE (200 mL) and sat. NH₄Cl (150 mL). Theorganic layer was separated, washed with 25 mL of water and 25 mL ofsat. NH₄Cl, dried over MgSO₄, filtered and evaporated to dryness to give20.0 g title compound as a solid (100%). ¹H NMR (400 MHz, CDCl₃) δ ppm1.56 (s, 9H) 6.47 (d, J=16 Hz, 1H) 7.58 (d, J=16 Hz, 1H) 7.61 (d, J=8Hz, 2H) 7.68 (d, J=8 Hz, 2H).

Intermediate 10 trans-tert-butyl2-(4-cyanophenyl)cyclopropanecarboxylate

Trimethylsulfoxonium iodide (37.9 g, 172.4 mmol) was dissolved in DMSO(450 mL) under nitrogen. Sodium tert-butoxide (16.5 g, 172.4 mmol) wasadded and the resultant mixture was stirred at rt for 2 h. Intermediate9 (20 g, 86.2 mmol) was added and the reaction mixture was stirred at rtfor 16 h. The reaction mixture was diluted by sequential addition ofMTBE (500 mL) and brine (300 mL). The organic layer was separated, driedover MgSO₄, filtered and evaporated to dryness. The crude product waspurified by flash chromatography (silica, heptane/EtOAc 95:5 to 90:10),giving 11.6 g title compound (54%) as a solid. ¹H NMR (400 MHz, CDCl₃) δppm 1.29-1.23 (m, 1H) 1.49 (s, 9H) 1.57-1.69 (m, 1H) 1.83-1.96 (m, 1H)2.40-2.53 (m, 1H) 7.18 (d, J=8 Hz, 2H) 7.57 (d, J=8 Hz, 2H).

Intermediate 11 trans-2-(4-bromophenyl)cyclopropyl)methanol

A solution of diethyl zinc (1.1 M, 695 mL, 765 mmol) in hexanes wasadded to a flame-dried 3-necked round bottom flask containing 450 mL ofDCM under nitrogen. The resulting solution was cooled to 0-5° C. TFA (59mL, 765 mmol) was added slowly to the cooled diethylzinc solution. Afterthe completion of addition, the resulting mixture was stirred for 20min. A solution of CH₂12 (62 mL, 765 mmol) in 50 mL of DCM was added tothe mixture. After an additional 20 min of stirring, a solution of3-(4-bromophenyl)prop-2-en-1-ol (81.6 g, 382.9 mmol) in 450 mL of DCMwas added. After completing addition, the reaction mixture was warmed tort and stirred for 2 h. Excess reagent was quenched by slow addition of500 mL of 1 M HCl. The top aq. layer was separated and extracted with200 mL of DCM. The combined organic extracts were washed with 500 mL ofa mixture of sat. NH₄Cl and NH₄OH (9:1 v/v), dried over MgSO₄, filteredand concentrated under reduced pressure. The crude was purified by flashcolumn chromatography (silica, heptane/EtOAc 10:1), giving 76.1 g titlecompound as a solid (87.5%). ¹H NMR (400 MHz, CDCl₃) δ ppm 0.90-1.00 (m,2H) 1.36-1.48 (m, 1H) 1.75-1.85 (m, 1H) 3.62 (t, J=6 Hz, 2H) 6.95 (d,J=8.5 Hz, 2H) 7.38 (d, J=8.5 Hz, 2H).

Intermediate 12 trans-4-(2-(hydroxymethyl)cyclopropyl)benzonitrile

A round bottom flask was charged with Intermediate 11 (10.0 g, 44 mmol),dimethylacetamide (125 mL), potassium hexacyanferrate (II) trihydrate(24.2 g, 22 mmol), palladium (II) acetate (1.3 g, 2.2 mmol), DABCO (1.3g, 4.4 mmol), and sodium carbonate (12.2 g, 44 mmol). The resultingmixture was heated to 150° C. under nitrogen for 17 h. The reactionmixture was cooled to rt and filtered through a pad of silica gel. Thepad was washed with EtOAc (200 mL). The combined filtrate and washingwere diluted with more EtOAc (200 mL), washed with brine (3×100 mL),dried over MgSO₄, filtered and concentrated under reduced pressure. Thecrude was purified by column chromatography (silica, DCM/MeOH 99:1) togive 10.5 g title compound (55%). ¹H NMR (400 MHz, CDCl₃) δ ppm1.00-1.15 (m, 2H) 1.47-1.58 (m, 1H) 1.88-1.94 (m, 1H) 3.56-3.76 (m, 2H)7.15 (d, J=8.5 Hz, 2H) 7.55 (d, J=8.5 Hz, 2H).

Intermediate 13 First Methodtrans-2-(4-cyanophenyl)cyclopropanecarboxylic acid

Intermediate 12 (11.2 g, 64.7 mmol) was dissolved in acetone (100 mL).The solution was cooled to −10° C. Jones reagent (65 mL) was added overa period of 30 min. After completing addition, the reaction was warmedto rt and then quenched by adding 2-propanol (100 mL). The resultingmixture was diluted with EtOAc (200 mL). MgSO₄ was added and stirringwas continued for another 30 min. The mixture was filtered and thefiltrate was concentrated under reduced pressure. The residue wasredissolved in EtOAc (200 mL), washed with 2×75 mL of water, dried overMgSO₄, filtered and concentrated under reduced pressure. The crude waspurified by trituration with EtOAc (20 mL) to afford 5.2 g titlecompound (43%) as a solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.39-1.46 (m,1H) 1.47-1.55 (m, 1H) 1.90-1.98 (m, 1H) 2.45-2.55 (m, 1H) 7.38 (d, J=8.2Hz, 2H) 7.73 (d, J=8.2 Hz, 2H).

Preparation of Jones Reagent:

Jones reagent was prepared by dissolving 26.7 g of CrO₃ in 23 mLconcentrated H₂SO₄ and diluting the mixture to 100 mL with water.

Intermediate 13 Second Methodtrans-2-(4-cyanophenyl)cyclopropanecarboxylic acid

Intermediate 10 (11.6 g, 47.7 mmol) was dissolved in MeOH (55 mL). Asolution of NaOH (5.7 g, 143.1 mmol) in water (30 mL) was added and theresultant mixture was heated at 70° C. for 4 h. After cooling to rt, themixture was concentrated to one-third its volume and diluted by theaddition of 50 mL of 0.5 M NaOH. The resultant mixture was washed with2×25 mL of MTBE. The aq. layer was separated and acidified by additionof concentrated HCl until pH 1. The acidified aq. phase was extractedwith 2×50 mL of EtOAc. The combined organic extracts were dried overMgSO₄, filtered and evaporated to dryness. The crude was purified byflash chromatography (silica, DCM:MeOH 99:1 to 90:10), giving 3.1 gtitle compound (36.4%) as a solid. ¹H NMR (400 MHz, CDCl₃) δ ppm1.37-1.46 (m, 1H) 1.47-1.55 (m, 1H) 1.87-1.98 (m, 1H) 2.43-2.49 (m, 1H)7.38 (d, J=8 Hz, 2H) 7.74 (d, J=8 Hz, 2H) 12.43 (s, 1H).

Intermediate 14 trans-2-(4-carbamoylphenyl)cyclopropanecarboxylic acid

Intermediate 13 (3.4 g, 18.16 mmol) was dissolved in tBuOH (90 mL).Grounded KOH (5.10 g, 90.81 mmol) was added, the reaction mixture washeated to 70° C. overnight, cooled to rt and concentrated under reducedpressure. The residue was redissolved in water and washed with EtOAc.The aq. phase was acidified to pH 4-5 with 1 M HCl. The precipitate wasfiltered and dried under vacuum to give 3.06 g title compound (82%) as asolid. The product was used in the next step without furtherpurification. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.42 (ddd, J=8.50, 6.35,4.69 Hz, 1H) 1.55-1.62 (m, 1H) 1.91 (ddd, J=8.50, 5.37, 4.10 Hz, 1H)2.52 (ddd, J=9.18, 6.25, 4.10 Hz, 1H) 7.20-7.26 (m, 2H) 7.76-7.83 (m,2H); MS m/z 206.22 [M+H]⁺ (ES+).

Intermediate 15 (R)-tert-butyl4-(trans-2-(4-carbamoylphenyl)cyclopropanecarbonyl)-3-methylpiperazine-1-carboxylate

Intermediate 14 (450 mg, 2.19 mmol) was dissolved in DMF (20 mL). DIPEA(1.149 mL, 6.58 mmol) was added, followed by HOBT (444 mg, 3.29 mmol),EDC (631 mg, 3.29 mmol) and intermediate 3 (527 mg, 2.63 mmol). Thereaction mixture was stirred at rt for 2 days, concentrated underreduced pressure, redissolved in EtOAc, washed with 1M HCl and sat.NaHCO₃, dried over MgSO₄, filtered and concentrated under reducedpressure to give title compound as a solid. The crude product was usedin the next step without further purification. MS m/z 388.34 [M+H]⁺(ESI).

Intermediate 16 (S)-tert-butyl4-(trans-2-(4-carbamoylphenyl)cyclopropanecarbonyl)-3-methylpiperazine-1-carboxylate

Intermediate 14 (450 mg, 2.19 mmol) was dissolved in DMF (20 mL). DIPEA(1.149 mL, 6.58 mmol) was added, followed by HOBT (444 mg, 3.29 mmol),EDC (631 mg, 3.29 mmol) and intermediate 6 (527 mg, 2.63 mmol). Themixture was stirred at rt overnight, concentrated under reducedpressure, redissolved in EtOAc washed with 1M HCl and sat. NaHCO₃, driedover MgSO₄, filtered and concentrated under reduced pressure to givetitle compound as a gum. The crude product was used in the next stepwithout further purification. MS m/z 388.31 [M+H]⁺ (ESI).

Intermediate 17 (R)-tert-butyl4-(trans-2-(4-carbamoylphenyl)cyclopropanecarbonyl)-3-ethylpiperazine-1-carboxylate

Intermediate 14 (300 mg, 1.46 mmol) was dissolved in DMF (15 mL). DIPEA(0.766 mL, 4.39 mmol) was added, followed by HOBT (296 mg, 2.19 mmol),EDC (420 mg, 2.19 mmol) and (R)-tert-butyl3-ethylpiperazine-1-carboxylate (376 mg, 1.75 mmol). The mixture wasstirred at rt for 2 h, concentrated under reduced pressure, redissolvedin DCM, washed with sat NaHCO₃, dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude material was purified onpreparative HPLC UV using the long high pH shallow gradient method(Mobile phase: 30-50% B; A: H₂O with 10 mM NH₄CO₃ and 0.375% NH₄OH v/v,B: CH₃CN, 30 min run) on XBridge Prep C18 OBD, 50×250 mm, 10 μm, Watersreverse phase column, giving 470 mg title compound (80%) as a whitecrystalline solid. ¹H NMR (400 MHz, CD₃OD) δ ppm 0.72 (t, J=7.42 Hz, 1H)0.84-1.00 (m, 2H) 1.34-1.44 (m, 1H) 1.46 (s, 9H) 1.50-1.80 (m, 3H)2.24-2.58 (m, 2H) 2.97 (br. s., 3H) 3.92-4.11 (m, 2.5H) 4.11-4.27 (m,0.5H) 4.28-4.39 (m, 0.5H) 4.43-4.56 (m, 0.5H) 7.21-7.30 (m, 2H) 7.80 (d,J=8.59 Hz, 2H); MS m/z 402.33 [M+H]⁺ (ESI).

Intermediate 18 (S)-tert-butyl4-(trans-2-(4-carbamoylphenyl)cyclopropanecarbonyl)-3-ethylpiperazine-1-carboxylate

Intermediate 14 was dissolved in DMF (15 mL). DIPEA (0.766 mL, 4.39mmol) was added, followed by HOBT (296 mg, 2.19 mmol), EDC (420 mg, 2.19mmol) and (S)-tert-butyl 3-ethylpiperazine-1-carboxylate (376 mg, 1.75mmol). The mixture was stirred at rt for 2 h, concentrated under reducedpressure, redissolved in DCM, washed with sat. NaHCO₃, dried over MgSO₄,filtered and concentrated under reduced pressure. The crude material waspurified on preparative HPLC UV using the long high pH shallow gradientmethod (Mobile phase: 30-50% B; A: H₂O with 10 mM NH₄CO₃ and 0.375%NH₄OH v/v, B: CH₃CN, 30 min run) on XBridge Prep C18 OBD, 50×250 mm, 10μm, Waters reverse phase column, giving 455 mg title compound (77%) as awhite crystalline solid. ¹H NMR (400 MHz, CD₃OD) δ ppm 0.72 (t, J=7.42Hz, 1H) 0.82-0.01 (m, 2H) 1.34-1.42 (m, 1H) 1.45 (s, 9H) 1.50-1.79 (m,3H) 2.25-2.50 (m, 2H) 2.73-3.20 (m, 3H) 3.91-4.11 (m, 2.5H) 4.19 (br.s., 0.5H) 4.33 (br. s., 0.5H) 4.50 (br. s., 0.5H) 7.19-7.34 (m, 2H) 7.81(d, J=8.59 Hz, 2H); MS m/z 402.32 [M+H]⁺ (ESI).

Intermediate 19 tert-butyl4-(trans-2-(4-carbamoylphenyl)cyclopropanecarbonyl)-3,3-dimethylpiperazine-1-carboxylate

Intermediate 14 was dissolved in DMF (20 mL). DIPEA (1.021 mL, 5.85mmol) was added, followed by HOBT (395 mg, 2.92 mmol), EDC (561 mg, 2.92mmol) and tert-butyl 3,3-dimethylpiperazine-1-carboxylate (587 mg, 2.34mmol). The reaction mixture was stirred at rt overnight, concentratedunder reduced pressure, redissolved in DCM, washed with 1M HCl and satNaHCO₃, dried over MgSO₄, filtered and concentrated under reducedpressure. The crude material was purified on preparative HPLC UV usingthe long high pH shallow gradient method (Mobile phase: 30-50% B; A: H₂Owith 10 mM NH₄CO₃ and 0.375% NH₄OH v/v, B: CH₃CN, 30 min run) on XBridgePrep C18 OBD, 50×250 mm, 10 μm, Waters reverse phase column, giving 412mg title compound (52.6%) as a solid. ¹H NMR (400 MHz, CDCl₃) δ ppm1.22-1.35 (m, 1H) 1.38-1.55 (m, 9H) 1.71 (br. s., 1H) 1.94 (br. s., 1H)2.47 (br. s., 1H) 2.88 (s, 3H) 2.96 (s, 3H) 3.32-3.59 (m, 4H) 3.65-3.85(m, 2H) 5.77 (br. s., 1H) 6.16 (br. s., 1H) 7.17 (d, J=8.20 Hz, 2H) 7.75(d, J=8.20 Hz, 2H); MS m/z 402.21 [M+H]⁺ (ESI).

Intermediate 204-(trans-2-((R)-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide

Intermediate 15 (849 mg, 2.19 mmol) was dissolved in DCM (10.0 mL). TFA(5.00 mL) was added and the reaction mixture stirred at rt for 30 min.Volatiles were evaporated under reduced pressure to give a yellow gum.The crude material was used in the next step without purification. ¹HNMR (400 MHz, CD₃OD) δ ppm 1.33 (d, J=7.03 Hz, 3H) 1.37-1.52 (m, 3H)1.65 (br. s., 1H) 2.26-2.39 (m, 1H) 2.51 (br. s., 1H) 3.11 (br. s., 1H)3.21-3.45 (m, 4H) 7.27 (d, J=8.20 Hz, 2H) 7.81 (d, J=8.20 Hz, 2H).

Intermediate 214-(trans-2-((S)-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide

Intermediate 16 (849 mg, 2.19 mmol) was dissolved in DCM (10 mL). TFA(5.00 mL) was added and the reaction mixture stirred at rt for 30 min.Volatiles were evaporated under reduced pressure to give a yellow gum.The crude material was used in the next step without purification. ¹HNMR (400 MHz, CD₃OD) δ ppm 1.28-1.37 (m, 3H) 1.37-1.52 (m, 3H) 1.65 (br.s., 1H) 2.28-2.39 (m, 1H) 2.51 (br. s., 1H) 3.10 (br. s., 1H) 3.38 (m,4H) 7.27 (d, J=8.20 Hz, 2H) 7.81 (d, J=8.20 Hz, 2H).

Intermediate 224-(trans-2-((R)-2-ethylpiperazine-1-carbonyl)cyclopropyl)benzamide

Intermediate 17 (445 mg, 1.11 mmol) was dissolved in DCM (5 mL). TFA(2.50 mL) was added and the reaction mixture stirred at rt for 30 min.Volatiles were evaporated under reduced pressure to give a yellow gum.The crude material was used for the next step without purification. 1HNMR (400 MHz, CD₃OD) δ ppm 0.68-0.84 (m, 1.5H) 0.85-1.05 (m, 3.5H)1.39-1.50 (m, 1.5H) 1.66-1.80 (m, 0.5H) 2.26-2.50 (m, 2H) 3.01-3.11 (m,1H) 3.32-3.43 (m, 4H) 4.43-4.82 (m, 2H) 7.21-7.31 (m, 2H) 7.77-7.86 (m,2H).

Intermediate 234-(trans-2-((S)-2-ethylpiperazine-1-carbonyl)cyclopropyl)benzamide

Intermediate 18 (429 mg, 1.07 mmol) was dissolved in DCM (5 mL). TFA(2.50 mL) was added and the reaction mixture stirred at rt for 1 h.Volatiles were evaporated under reduced pressure to give a yellow gum.The crude material was used for the next step without purification. 1HNMR (400 MHz, CD₃OD) δ ppm 0.68-0.85 (m, 1.5H) 0.85-1.09 (m, 3.5H) 1.44(ddd, J=8.20, 6.45, 4.49 Hz, 1.5H) 1.67-1.81 (m, 0.5H) 2.26-2.50 (m, 2H)3.01-3.15 (m, 1H) 3.32-3.43 (m, 4H) 4.45-4.84 (m, 2H) 7.17-7.34 (m, 2H)7.81 (d, J=8.59 Hz, 2H).

Intermediate 244-(trans-2-(2,2-dimethylpiperazine-1-carbonyl)cyclopropyl)benzamide

Intermediate 19 (392 mg, 0.98 mmol) was dissolved in DCM (7 mL). TFA(3.50 mL) was added and the reaction mixture stirred at rt for 30 min.Volatiles were evaporated under reduced pressure to give a yellow gum.The crude material was used in the next step without purification. ¹HNMR (400 MHz, CD₃OD) δ ppm 1.38 (ddd, J=8.40, 6.25, 4.49 Hz, 1H)1.50-1.63 (m, 1H) 2.21-2.28 (m, 1H) 2.43 (ddd, J=9.08, 6.15, 4.30 Hz,1H) 2.86 (s, 3H) 3.00 (s, 3H) 3.19 (s, 2H) 3.37 (t, J=5.66 Hz, 2H) 3.90(q, J=5.47 Hz, 2H) 7.26 (d, J=8.20 Hz, 2H) 7.80 (d, J=8.20 Hz, 2H); MSm/z 302.28 [M+H]⁺ (ESI).

Intermediate 25 (E)-methyl 3-(3-cyanophenyl)acrylate

Methyl 2-(dimethoxyphosphoryl)acetate (20.83 g, 114.39 mmol) wasdissolved in THF (500 mL). Sodium hydride (4.58 g, 114.39 mmol) wasadded in small portions. 3-formylbenzonitrile (10 g, 76.26 mmol) wasadded dissolved in 50 mL of THF and the reaction mixture was stirred atrt for 2 h. The reaction mixture was diluted with heptane, washed withH₂O, dried over sodium sulfate, filtered and concentrated under reducedpressure. The resulting solid was triturated in heptane, filtered,washed with heptane and dried under vacuum, giving 13.26 g titlecompound (93%) as a white powder. ¹H NMR (400 MHz, CDCl₃) δ ppm 3.83 (s,3H) 6.50 (d, J=16.02 Hz, 1H) 7.52 (t, J=7.81 Hz, 1H) 7.61-7.84 (m, 4H).

Intermediate 26 Trans-methyl 2-(3-cyanophenyl)cyclopropanecarboxylate

Trimethylsulfoxonium iodide (4.23 g, 19.23 mmol) was dissolved in DMSO(160 mL). Potassium tert-butoxide (2.158 g, 19.23 mmol) was added andthe mixture was heated until complete dissolution. Intermediate 25 (3.0g, 16.03 mmol) was added and the reaction mixture stirred 4 h at rt,concentrated under reduced pressure, diluted with EtOAc, washed withH₂O, dried over MgSO₄, filtered and concentrated under reduced pressure.The crude material was purified on silica gel by MPLC using 0-5% MeOH inDCM to provide 0.771 g title compound (23.91%) as a solid. ¹H NMR (400MHz, CDCl₃) δ ppm 1.34 (ddd, J=8.50, 6.35, 4.69 Hz, 1H) 1.63-1.72 (m,1H) 1.93 (ddd, J=8.50, 5.37, 4.10 Hz, 1H) 2.56 (ddd, J=9.28, 6.35, 4.30Hz, 1H) 3.74 (s, 3H) 7.32-7.44 (m, 3H) 7.48-7.54 (m, 1H); MS m/z 201.92[M+H]⁺ (ESI).

Intermediate 27 trans-2-(3-carbamoylphenyl)cyclopropanecarboxylic acid

Intermediate 26 (771 mg, 3.83 mmol) was dissolved in tBuOH (80 mL).Ground KOH (1.075 g, 19.16 mmol) was added and the reaction mixture washeated to 70° C. overnight. After cooling to rt, the solid formed wasfiltered and dissolved in H₂O. The aq. phase was acidified to pH 2-3with 2M HCl. The precipitate formed was filtered and dried under vacuumto provide 481 mg title compound (61.2%) as a solid. ¹H NMR (400 MHz,CD₃OD) δ ppm 1.43 (ddd, J=8.40, 6.45, 4.69 Hz, 1H) 1.52-1.62 (m, 1H)1.85-1.95 (m, 1H) 2.53 (ddd, J=9.18, 6.45, 4.30 Hz, 1H) 7.31-7.44 (m,2H) 7.64 (t, J=1.76 Hz, 1H) 7.71 (ddd, J=7.23, 1.95, 1.76 Hz, 1H); MSm/z 205.91 [M+H]⁺ (ESI).

Intermediate 28 (R)-tert-butyl4-(trans-2-(3-carbamoylphenyl)cyclopropanecarbonyl)-3-methylpiperazine-1-carboxylate

Intermediate 27 (110 mg, 0.54 mmol) was dissolved in DMF (10 mL). DIPEA(0.281 mL, 1.61 mmol) was added, followed by HOBT (109 mg, 0.80 mmol),EDC (154 mg, 0.80 mmol) and intermediate 3 (129 mg, 0.64 mmol). Thereaction mixture was stirred at rt overnight, concentrated under reducedpressure, redissolved in EtOAc, washed with 1M HCl and sat. NaHCO₃,dried over MgSO₄, filtered and concentrated under reduced pressure togive 137 mg title compound (66.2%) as an orange gummy solid. The crudeproduct was used in the next step without further purification. MS m/z388.27 [M+H]⁺ (ESI).

Intermediate 29 (S)-tert-butyl4-(trans-2-(3-carbamoylphenyl)cyclopropanecarbonyl)-3-methylpiperazine-1-carboxylate

Intermediate 27 (110 mg, 0.54 mmol) was dissolved in DMF (10 mL). DIPEA(0.281 mL, 1.61 mmol) was added, followed by HOBT (109 mg, 0.80 mmol),EDC (154 mg, 0.80 mmol) and intermediate 6 (129 mg, 0.64 mmol). Thereaction mixture was stirred at rt overnight, concentrated under reducedpressure, redissolved in EtOAc, washed with 1M HCl and sat. NaHCO₃,dried over MgSO₄, filtered and concentrated under reduced pressure togive 133 mg title compound (64.1%) as an orange gummy solid. The crudeproduct was used in the next step without further purification. MS m/z388.27 [M+H]⁺ (ESI).

Intermediate 303-(trans-2-((R)-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide

Intermediate 28 (135 mg, 0.35 mmol) was dissolved in DCM (2.5 mL). TFA(1.25 mL) was added and the reaction mixture stirred at rt for 4.5 h.Volatiles were evaporated under reduced pressure to give a dark orangegummy solid. The crude material was used in the next step withoutpurification. 1H NMR (400 MHz, CD₃OD) δ ppm 1.23-1.49 (m, 5H) 1.61 (br.s., 1H) 2.31 (dq, J=8.74, 4.51 Hz, 1H) 2.51 (br. s., 1H) 2.86 (s, 1H)3.00 (s, 1H) 3.02-3.30 (m, 2H) 3.33-3.43 (m, 2H) 7.39 (d, J=4.69 Hz, 2H)7.65 (s, 1H) 7.71 (t, J=3.71 Hz, 1H).

Intermediate 313-(trans-2-((S)-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide

Intermediate 29 (130 mg, 0.34 mmol) was dissolved in DCM (2.5 mL). TFA(1.25 mL) was added and the reaction mixture stirred at rt for 4 h.Volatiles were evaporated under reduced pressure to give a dark orangegummy solid. The crude material was used for the next step withoutpurification. 1H NMR (400 MHz, CD₃OD) δ ppm 1.22-1.52 (m, 5H) 1.62 (br.s., 1H) 2.25-2.36 (m, 1H) 2.51 (br. s., 1H) 2.86 (s, 1H) 3.00 (s, 1H)3.05-3.30 (m, 3H) 3.34-3.44 (m, 1H) 7.39 (d, J=4.69 Hz, 2H) 7.65 (s, 1H)7.67-7.75 (m, 1H).

Intermediate 32 (R)-1-Cyclobutyl-3-methylpiperazine×2HCl

(R)-Boc-2-methylpiperazine (350 g, 1.71 moles, 98% w/w), which iscommercially available from Lanzhou Boc Chemical Co., was dissolved inEtOH (2.75 L) at t_(jacket)=20° C. Acetic acid (1.37 L) was added in oneportion followed by the addition of cyclobutanone (184 g, 2.57 moles).The charging vessel was rinsed with EtOH (250 mL) and the light yellowsolution was left stirring at t_(jacket)=20° C. for 1 h. NaBH(OAc)₃ (497g, 2.48 moles, 95% w/w) was added in 20 portions over 90 min. EtOH (340mL) was used for rinsing. The reaction mixture was left stirring for 2h. A sample was analyzed on GC using HP-5MS column (length 25 m, ID 0.32mm, Film 0.52 m) with a gradient method (2 min at 60° C., followed by25° C./min during 8 min then 2 min at 260° C.). Frontinlettemperature=200° C. using He as gas and a detector temperature=300° C.More NaBH(OAc)₃ (30 g, 0.14 moles) was added to complete the reactionwithin 1 h. The reaction mixture was cooled to t_(jacket)=0° C. beforequenching with 5M NaOH (5.5 L). EtOH was distilled off under vacuum att_(jacket)=50° C. The H₂O phase was extracted with toluene (5.5 L) att_(jacket)=20° C. The organic phase was combined with a second batch,started with (R)-Boc-2-methylpiperazine (300 g, 1.47 moles, 98% w/w).The combined organic phases were concentrated under vacuum att_(jacket)=50° C. to approximately 2 L. The obtained toluene solutionwith the intermediate can be stored at 5° C. for several days. Thetoluene solution was diluted with 2-propanol (2 L) at t_(jacket)=10° C.,and HCl in 2-propanol (1.06 L, 6.36 moles, 6M) diluted in 2-propanol (2L) was added over 30 min. The reaction solution was heated tot_(jacket)=48° C. HCl in 2-propanol (2.12 L, 12.72 moles, 6M) diluted in2-propanol (2 L) was added over 2 h at t_(inner)=46° C. The reactionsolution was kept at t_(jacket)=48° C. for an additional 3 h beforebeing cooled to t_(jacket)=0° C. over 1 h. A seed mixture (0.4 Lreaction solution with Intermediate 32 (0.2 g, 0.89 mmoles)) was added.The reaction mixture was left stirring at t_(jacket)=0° C. overnight andthe product was filtered off. Drying under vacuum at 40° C. gaveIntermediate 32 (620 g, 2.63 moles, 96.3% w/w), 83% yield. ¹H-NMR(DMSO-d₆): δ 12.46 (s, 1H), 10.13 (s, 2H), 3.35-3.74 (m, 6H), 3.09 (m,1H), 2.92 (m, 1H), 2.39 (m, 2H), 2.16 (m, 2H), 1.72 (m, 2H), 1.32 (d,3H, J=6.4 Hz); ¹³C-NMR (DMSO-d₆): δ 58.50, 49.62, 48.13, 44.30, 24.48,24.38, 15.25, 13.26.

Intermediate 33 (R)-1-(4-Bromo-phenyl)-2-chloro-ethanol

Borane dimethylsulfide (2.0 kg, 24.8 moles, 94% w/w) was mixed intoluene (8 L) at t_(jacket)=20° C. (R)-(+)-Methyl-CBS-oxazaborolidine(2.6 kg, 2.74 moles, 1M) as a toluene solution was added. The chargingvessel was rinsed with toluene (0.5 L) and t_(jacket) was set to 45° C.1-(4-Bromo-phenyl)-2-chloro-ethanone (7.84 kg, 33.6 moles), which iscommercially available from Jiangyan Keyan Fine Chemical Co. Ltd, wasdissolved in 2-MeTHF (75 L) in a separate vessel and when t_(inner) wasabove 40° C. in the first vessel, the 2-MeTHF solution was added during3 h. The latter vessel was rinsed with 2-MeTHF (2 L) and added to thereaction mixture, which was left stirring at t_(jacket)=45° C. for 1 h.Analysis of a sample on HPLC indicated full conversion at this pointusing the following gradient method (mobile phase 20-95% B; A: 5% CH₃CNin H₂O with 0.1% TFA, B: 95% CH₃CN in H₂O with 0.085% TFA, 10 min run)on Chromolith Performance RP-18e, 4.6×100 mm. The reaction mixture wascooled to t_(jacket)=10° C. before slow quench with MeOH (36 L). Thefirst liter of MeOH was added during 30 min. and the rest duringadditional 30 min. MeOH was distilled off under vacuum at t_(jacket)=50°C. The organic solution left was cooled to t_(jacket)=20° C., washedwith 1M HCl in H₂O (7 L conc HCl+73 L H₂O) and concentrated under vacuumat t_(jacket)=50° C. to approximately 40 L. Intermediate 33 obtained ina 2-MeTHF solution can be stored at 10° C. for 20 h or used directly inthe next synthetic step.

Intermediate 34 (R)-2-(4-Bromo-phenyl)-oxirane

Aliquat® 175 (methyl tributyl ammonium chloride) (1.12 kg, 4.75 moles)was added to Intermediate 33 as a 2-MeTHF solution (33.6 moles, 40 L) att_(jacket)=20° C. NaOH (5.1 kg, 57.4 moles, 45% w/w) diluted in H₂O (2L) was added during 20 min. The reaction mixture was left stirring att_(jacket)=20° C. for 2 h. Analysis of a sample on HPLC indicated fullconversion at this point using the following gradient method (mobilephase 20-95% B; A: 5% CH₃CN in H₂O with 0.1% TFA, B: 95% CH₃CN in H₂Owith 0.085% TFA, 10 min run) on Chromolith Performance RP-18e, 4.6×100mm. The aq. phase was separated off and the organic phase washed withH₂O (2×25 L). 2-MeTHF (25 L) was added and the organic phaseconcentrated under vacuum at t_(jacket)=50° C. to approximately 30 L.Intermediate 34 obtained in a 2-MeTHF solution, can be stored at 5° C.for 140 h or used directly in the next synthetic step.

Intermediate 35 First Method(1S,2S)-2-(4-Bromo-phenyl)-cyclopropanecarboxylic acid

Triethyl phosphonoacetate (10.5 L, 51.9 moles, 98% w/w) was dissolved in2-MeTHF (14 L) at t_(jacket)=−20° C. Hexyl lithium in hexane (21 L, 48.3moles, 2.3 M) was added at a rate to maintain t_(inner) below 0° C. Thecharging vessel was rinsed with 2-MeTHF (3 L) and the reaction solutionwas left stirring at t_(jacket)=10° C. Intermediate 34 as a 2-MeTHFsolution (33.6 moles, 30 L) was added during 20 min. The charging vesselwas rinsed with 2-MeTHF (2 L) and the reaction solution was leftstirring at t_(jacket)=65° C. for at least 16 h with the last 3 h att_(jacket)=75° C. Analysis of a sample on HPLC using the followinggradient method (mobile phase 20-95% B; A: 5% CH₃CN in H₂O with 0.1%TFA, B: 95% CH₃CN in H₂O with 0.085% TFA, 10 min run) on ChromolithPerformance RP-18e, 4.6×100 mm indicated full conversion to theintermediate (1S,2S)-2-(4-bromo-phenyl)-cyclopropanecarboxylic acidethyl ester. The reaction solution was cooled to t_(jacket)=20° C. NaOH(7.6 kg, 85.5 moles, 45% w/w) diluted in H₂O (12 L) was added over 20min. The reaction solution obtained was left stirring at t_(jacket)=60°C. for at least 2 h. Analysis of a sample on HPLC indicated fullconversion at this point using the following gradient method (mobilephase 20-95% B; A: 5% CH₃CN in H₂O with 0.1% TFA, B: 95% CH₃CN in H₂Owith 0.085% TFA, 10 min run) on Chromolith Performance RP-18e, 4.6×100mm. The reaction solution was cooled to t_(jacket)=20° C., the aq. phasewas separated off and the organic phase was extracted with H₂O (37 L).The combined aq. phases were acidified to pH<3.5 with H₃PO₄ (9 L, 131moles, 85% w/w) diluted in H₂O (12.5 L). Only 17 L of the diluted H₃PO₄(aq) was used to achieve the pH<3.5. The acidic aq. phase was extractedwith 2-MeTHF (2×15 L). The combined organic phases including rinsingwith 2-MeTHF (2 L) were concentrated under vacuum at t_(jacket)=50° C.to approximately 11 L. The 2-MeTHF solution was diluted with EtOH (14.5L) at t_(jacket)=35° C. and H₂O (16 L) was added over 20 min. Thereaction solution was cooled to t_(jacket)=28° C. Seed (16 g, 0.066moles) was added and the solution was stirred for 2 h at t_(jacket)=28°C. The reaction mixture was cooled to t_(jacket)=0° C. over 6 h and leftstirring for at least 1 h. Additional H₂O (8 L) was added during 40 min.and the product was filtered off and washed with cold H₂O (10 L). Dryingunder vacuum at 40° C. gave 6.18 kg Intermediate 35 (21.5 moles, 84%w/w), 64% yield over four steps from 7.84 kg1-(4-bromo-phenyl)-2-chloro-ethanone (33.6 moles).

Recrystallization of Intermediate 35: Two batches of Intermediate 35(6.18+7.04 kg) were mixed in EtOH (52 L) and heated at t_(jacket)=70° C.H₂O (52 L) was added. The reaction solution was cooled to t_(jacket)=30°C. over 2.5 h. H₂O (16 L) was added during 20 min. and thecrystallization was cooled to t_(jacket)=20° C. during 3 h. The productwas filtered off and washed with a mixture of H₂O (8 L) and EtOH (2 L).Drying under vacuum at 40° C. gave 10.0 kg Intermediate 35 (41.5 moles,88% w/w), which was redissolved in toluene (39 L) and isooctane (57 L)at t_(jacket)=60° C. A clear solution was obtained. The reactionsolution was cooled to t_(jacket)=45° C. and left stirring for 1 h, thencooled to t_(jacket)=20° C. over 2 h. The product was filtered off andwashed with a mixture of toluene (4 L) and isooctane (36 L) in twoportions. Drying under vacuum at 40° C. gave 7.4 kg Intermediate 35(29.8 moles, 97% w/w), 44% yield over four steps from 7.84+7.93 kg1-(4-bromo-phenyl)-2-chloro-ethanone (67.5 moles). ¹H-NMR (DMSO-d₆): δ12.36 (s, 1H), 7.44 (d, 2H, J=8 Hz), 7.13 (d, 2H, J=8 Hz), 2.39 (m, 1H),1.81 (m, 1H), 1.43 (m, 1H), 1.33 (m, 1H); ¹³C-NMR (DMSO-d₆): δ 173.76,139.88, 131.20, 128.24, 119.14, 24.73, 24.31, 16.78; LC-MS (ESI): m/z239 (M−1 (Br⁷⁹)) and 241 (M−1 (Br⁸¹)). R_(t)=5.03 min with theanalytical method (mobile phase: 5-90% B; A: H₂O with 0.1% formic acid,B: CH₃CN, 8.6 min run) on Xbridge C18, 3.0×50 mm, 2.5 μm particle size.

Intermediate 35 Second Method(1S,2S)-2-(4-Bromo-phenyl)-cyclopropanecarboxylic acid

To a stirred solution of (trans)-2-(4-bromophenyl)cyclopropanecarboxylicacid (6.52 g, 27.04 mmol), which can be prepared in accordance with theprocess set forth on page 82 of WO 2009/024823, in 400 ml of EtOH wasadded a solution of (R)-(+)-1-(1-Naphthyl)ethylamine (4.63 g, 4.37 mL,27.04 mmol) in 100 ml of EtOH followed by 25 ml of H₂O. This was stirredat rt for about 4 h. The solid was collected by filtration and washedwith 40 ml of cold EtOH/H₂O (20/1) to provide 3.18 g of salt as a whitesolid (58% recovery) equivalent to 1.86 g of free acid. This was takenup in 2 N NaOH and extracted 5 times with EtOAc. The aq. phase wasplaced on a rotary evaporator to remove the remaining EtOAc. Theresulting clear solution was transferred to an erlenmeyer flask, cooledin an ice bath, and conc. HCl was added dropwise while stirring to pH 4.The resulting solid was collected by filtration providing 1.63 g ofIntermediate 35. The product was analyzed by chiral SFC (UV detection)using isocratic method (mobile phase: 25% MeOH with 0.1% DMEA,supercritical CO₂) on ChiralPak AD-H, 10×250 mm, 5 μm particle size,giving an enantiomeric purity of >95%, R_(t)=3.88 min (isomer 1) and4.79 min (isomer 2). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.37 (ddd, J=8.20,6.64, 4.69 Hz, 1H), 1.67 (ddd, J=9.28, 5.08, 4.79 Hz, 1H), 1.87 (ddd,J=8.50, 4.69, 4.39 Hz, 1H), 2.48-2.63 (m, 1H), 6.87-7.06 (m, 2H),7.37-7.46 (m, 2H).

Intermediate 36 (1S,2S)-2-(4-Cyano-phenyl)-cyclopropanecarboxylic acid

Intermediate 35 (first method) (3.7 kg, 14.9 moles, 97% w/w) andzinc-dust (98%+, <10 μm) (99 g, 1.51 moles) were mixed with DMF (13.5 L)and the slurry was stirred at t_(jacket)=20° C. The mixture was inertedand left with N₂ pressure of 0.1-0.2 bar.Bis(tri-t-butylphosphine)-palladium (0) (27.5 g, 0.054 moles) was addedto the slurry, and the vessel was inerted and left with N₂ pressure of0.1-0.2 bar. The mixture was heated to t_(jacket)=45° C., Zn(CN)₂ (1.0kg, 8.52 moles) was added to the suspension in one portion, and thesystem was inerted and left with N₂ pressure of 0.1-0.2 bar (N.B.Cyanide salts are highly toxic). The resulting mixture was heated tot_(jacket)=75° C. and stirred for at least 2 h. Analysis of a sample onHPLC indicated full conversion at this point using the followinggradient method (mobile phase 20-95% B; A: 5% CH₃CN in H₂O with 0.05%formic acid, B: 95% CH₃CN in H₂O with 0.05% formic acid, 8 min run) onChromolith Performance RP-18e, 4.6×100 mm. The reaction mixture wascooled to t_(jacket)=20° C. Thiol-functionalized silica (Silicycle,SiliaBond Thiol) (1.07 kg, 28% w/w) was added and the vessel wasinerted. The reaction mixture was stirred for at least 36 h att_(jacket)=20° C. The scavenger was filtered off via a filter withactivated charcoal or equivalent (pall-filter). The vessel and thefilter system were washed with 2-MeTHF (53 L). The filtrate and washingswere combined and stirred at t_(jacket)=5° C. A pale yellow liquidresulted. NaCl (3.5 kg) in H₂O (16.4 L) was added during 15 min. at sucha rate so the inner temperature remained below 15° C. The resultingreaction mixture was heated to t_(jacket)=₄₅° C. and the aq. phase wasseparated off. The organic phase was washed with NaHSO₄×H₂O in H₂O(2×(2.87 kg+16.4 L)) and NaCl in H₂O (3.5 kg+16.4 L). The organic phasewas cooled to t_(jacket)=10° C. and NaOH (1.54 kg, 19.3 moles, 50% w/w)diluted in H₂O (41 L) was added during 45 min. The resulting reactionmixture was heated to t_(jacket)=30° C. and the organic phase wasseparated off. The aq. phase was stirred at t_(jacket)=20° C. and pHadjusted to 6.5 with H₃PO₄ (0.90 kg, 7.81 moles, 85% w/w) diluted in H₂O(5.3 L) at a rate that maintained the inner temperature below 25° C.2-MeTHF and H₂O were distilled off under vacuum until a volume 85-90% ofthe volume prior to distillation, approximately 8 L. The reactionmixture was cooled to t_(jacket)=0° C. and continued charging off H₃PO₄(1.17 kg, 10.1 moles, 85% w/w) diluted in H₂O (8.2 L) until pH=4. Theslurry was left stirring overnight at t_(jacket)=10° C. The product wasfiltered off, washed with H₂O (2×4 L). Drying under vacuum at 40° C.gave Intermediate 36 (2.24 kg, 11.2 moles, 93.2% w/w), 75% yield. ¹H-NMR(DMSO-d₆): δ 12.45 (s, 1H), 7.72 (d, 2H, J=8 Hz), 7.37 (d, 2H, J=8 Hz),2.50 (m, 1H), 1.94 (m, 1H), 1.50 (m, 1H), 1.42 (m, 1H); ¹³C-NMR(DMSO-d₆): δ 173.51, 146.68, 132.27, 126.93, 118.97, 108.85, 25.16,25.04, 17.44; LC-MS (ESI): m/z 186 (M−1). R_(t)=3.63 min with theanalytical method (mobile phase: 5-90% B; A: H₂O with 0.1% formic acid,B: CH₃CN, 8.6 min run) on Xbridge C18, 3.0×50 mm, 2.5 μm particle size.

Intermediate 37 (1S,2S)-2-(4-Carbamoyl-phenyl)-cyclopropanecarboxylicacid

Intermediate 36 (4.46 kg, 22.0 moles, 92.5% w/w) was mixed in H₂O (40 L)at t_(jacket)=30° C. NaOH (2.25 kg, 28.1 moles, 50% w/w) diluted in H₂O(6 L) was added at such a rate so t_(inner) remained below 35° C. Thecharging vessel was rinsed with H₂O (1 L). If the pH was not ≧12, moreNaOH was charged in the same concentration as previously. Hydrogenperoxide (4.89 kg, 50.3 moles, 35% w/w) was added at a rate to maintaint_(inner) below 35° C. The charging vessel was rinsed with H₂O (1 L) andthe reaction slurry was left stirring for 0.5-1.0 h. Analysis of asample on HPLC indicated full conversion at this point using thefollowing gradient method (mobile phase 20-95% B; A: 5% CH₃CN in H₂Owith 0.05% formic acid, B: 95% CH₃CN in H₂O with 0.05% formic acid, 8min run) on Chromolith Performance RP-18e, 4.6×100 mm. The reactionmixture was cooled to t_(jacket)=0° C. and left stirring for at least0.5 h when the temperature was reached. The sodium salt of Intermediate37 was filtered off and washed with cold H₂O (2×7 L). The solid wasslurry washed on the filter with NaHSO₄×H₂O (2.76 kg, 20.0 moles)diluted in H₂O (35 L). The slurry was kept stirring at t_(jacket)=0° C.for 1 h. If the pH was not <3.7, it was adjusted with NaHSO₄×H₂O in H₂O.The product was filtered off, washed with cold H₂O (3×14 L). Dryingunder vacuum at 40° C. gave Intermediate 37 (4.0 kg, 18.2 moles, 93.4%w/w), 83% yield. ¹H-NMR (DMSO-d₆): δ 12.40 (s, 1H), 7.94 (s, 1H), 7.79(d, 2H, J=8 Hz), 7.32 (s, 1H), 7.23 (d, 2H, J=8 Hz), 2.44 (m, 1H), 1.88(m, 1H), 1.47 (m, 1H), 1.39 (m, 1H); ¹³C-NMR (DMSO-d₆): δ 173.83,167.67, 143.94, 132.17, 127.68, 125.73, 25.21, 24.67, 17.11; LC-MS(ESI): m/z 206 (M+1). R_(t)=2.13 min with the analytical method (mobilephase: 5-90% B; A: H₂O with 0.1% formic acid, B: CH₃CN, 8.6 min run) onXbridge C18, 3.0×50 mm, 2.5 μm particle size.

Intermediate 38((1S,2S)-2-(4-bromophenyl)cyclopropyl)((R)-4-cyclobutyl-2-methylpiperazin-1-yl)methanone

To a solution of Intermediate 35 (second method) (5.87 g, 24.34 mmol) inDMF (120 mL) at 0° C. was added N,N-Diisopropylethylamine (21.20 mL,121.72 mmol), 1-Hydroxybenzotriazole (4.93 g, 36.52 mmol),N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (7 g, 36.52mmol) followed by Intermediate 32 (5.53 g, 24.34 mmol). The reaction wasstirred for 15 h then the reaction was concentrated and the residuetaken into EtOAc and washed with a saturated solution of NaHCO₃. The aq.phase was extracted twice with EtOAc and the combined organics werewashed with brine, dried over MgSO₄ filtered and concentrated. Theresulting oil was purified by normal phase chromatography using agradient of EtOAc/Heptane 20 to 100% on a 120 g Redisep column using anISCO Companion instrument providing Intermediate 38 (8.50 g, 93%) asclear glass, which solidified slowly on standing. ¹H-NMR (400 MHz,Methanol-d₄) δ ppm 1.27 (br. s., 3H) 1.38 (br. s., 1H) 1.48-1.58 (m, 1H)1.64-1.77 (m, 3H) 1.77-1.87 (m, 1H) 1.87-1.99 (m, 2H) 1.98-2.09 (m, 2H)2.14-2.22 (m, 1H) 2.34 (br. s., 1H) 2.63-2.76 (m, 2H) 2.85 (dddd,J=11.43, 3.61, 1.95, 1.76 Hz, 1H) 2.90-3.01 (m, 1H) 3.40 (br. s., 1H)4.03 (d, J=11.33 Hz, 1H) 4.31 (d, J=11.72 Hz, 1H) 4.39 (br. s., 1H) 4.64(br. s., 1H) 7.09 (d, J=8.20 Hz, 2H) 7.41 (d, J=8.59 Hz, 2H). Theproduct was analyzed on analytical HPLC MS using the high pH gradientmethod (mobile phase: 5-95% B; A: H₂O with 10 mM NH₄CO₃ and 0.375% NH₄OHv/v, B: CH₃CN, 2.25 min run) on X-Bridge C18, 2.1×30 mm, 5 μm particlesize. MS m/z 277.31 [M+H]+(ESI), R_(t)=2.10 min.

Intermediate 394-((1S,2S)-2-((R)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzonitrile

To a solution of Intermediate 38 (8.5 g, 22.53 mmol) in NMP (100 mL)while bubbling Ar was added Zinc (0.737 g, 11.26 mmol), Zinc cyanide(1.984 g, 16.90 mmol) anddichloro[1,1′-bis(di-t-butylphosphino)ferrocene]palladium(II) (0.335 g,0.45 mmol). This was heated at 100° C. for 20 h. Some starting materialwas still present, therefore heating was continued for a further 24 h.The reaction was cooled and concentrated under high vac. The materialwas taken into EtOAc and filtered through celite. The filtrate wasconcentrated, divided into two portions of equal weight, wherein eachportion was purified on a 120 g silica gel column eluting with agradient of EtOAc/heptane 50-100% providing Intermediate 39 (6.10 g,84%). The product was analyzed on analytical HPLC MS using the high pHgradient method (mobile phase: 5-95% B; A: H₂O with 10 mM NH₄CO₃ and0.375% NH₄OH v/v, B: CH₃CN, 2.25 min run) on X-Bridge C18, 2.1×30 mm, 5μm particle size. MS m/z 324.39 [M+H]⁺ (ESI), R_(t)=1.76 min.

1-28. (canceled)
 29. A method for treating a disorder selected fromcognitive deficits in schizophrenia, Alzheimer's disease, obesity,narcolepsy, pain, and attention deficit hyperactivity disorder, in awarm-blooded animal, comprising administering to said animal in need ofsuch treatment a therapeutically effective amount of at least onecompound of formula I, or enantiomers or diastereomers thereof, orpharmaceutically acceptable salts of formula I or enantiomers ordiastereomers thereof, or mixtures thereof:

wherein: R¹ is aryl, heteroaryl, —C₁-C₆alkyl-C₁-C₃alkoxy,—C₁-C₆alkyl-hydroxy, —C₁-C₆alkyl-C(═O)—NR¹¹R¹², —S(═O)₂NR¹¹R¹²,heterocycle, cyano, haloalkyl, —C(═O)NR¹¹R¹², alkoxy, or halogen; R² isC₁-C₆alkyl or C₃-C₆cycloalkyl; R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ areeach independently selected from H and C₁-C₃alkyl; and R¹¹ and R¹² areeach independently selected from H, —C₁-C₆alkyl,—C₁-C₃alkyl-C₁-C₃alkoxy, 5-membered heterocycloalkyl containing at leastone heteroatom selected from O and N, 6-membered heterocycloalkylcontaining at least one heteroatom selected from O and N,—(C₁-C₃alkyl)-(5-membered heteroaryl containing at least one heteroatomselected from O and N), —(C₁-C₃alkyl)-(6-membered heteroaryl containingat least one heteroatom selected from O and N), haloalkyl, or R¹¹, R¹²and the N to which they are attached come together to form aheterocycloalkyl selected from pyrrolidinyl, morpholinyl, piperidinyl,and piperazinyl, wherein said heterocycloalkyl is optionally substitutedby at least one substituent selected from —C₁-C₃alkyl and—C₁-C₆alkyl-C₁-C₃alkoxy; and provided: i) at least one of R³, R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, and R¹⁰ is a C₁-C₃alkyl; ii) formula I is not

 when R¹ is a —C(═O)NR¹¹R¹² group meta-attached to the phenyl, R² isisopropyl, and R¹¹ and R¹² are H; and iii) formula I is not in the cisconfiguration at the cyclopropane.
 30. The method according to claim 29,wherein said disorder is pain.
 31. The method according to claim 30,wherein said pain is peripheral neuropathic pain.
 32. The methodaccording to claim 29, wherein R¹ is —C(═O)NR¹¹R¹².
 33. The methodaccording to claim 32, wherein R¹¹ and R¹² are H.
 34. The methodaccording to claim 29, wherein R² is C₁-C₃alkyl.
 35. The methodaccording to claim 29, wherein R² is C₃-C₆cycloalkyl.
 36. The methodaccording to claim 29, wherein R² is isopropyl or cyclobutyl.
 37. Themethod according to claim 29, wherein R³ is C₁-C₃alkyl and R⁴, R⁵, R⁶,R⁷, R⁸, R⁹, and R¹⁰ are each independently selected from H.
 38. Themethod according to claim 37, wherein R³ is methyl.
 39. The methodaccording to claim 29, wherein R⁴ is C₁-C₃alkyl and R³, R⁵, R⁶, R⁷, R⁸,R⁹, and R¹⁰ are each independently selected from H.
 40. The methodaccording to claim 39, wherein R⁴ is methyl.
 41. The method according toclaim 29, wherein R⁵ is C₁-C₃alkyl and R³, R⁴, R⁶, R⁷, R⁸, R⁹, and R¹⁰are each independently selected from H.
 42. The method according toclaim 41, wherein R⁵ is methyl or ethyl.
 43. The method according toclaim 29, wherein R⁶ is C₁-C₃alkyl and R³, R⁴, R⁵, R⁷, R⁸, R⁹, and R¹⁰are each independently selected from H.
 44. The method according toclaim 43, wherein R⁶ is methyl or ethyl.
 45. The method according toclaim 29, wherein R³ and R⁴ are each independently selected fromC₁-C₃alkyl and R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ are each independentlyselected from H.
 46. The method according to claim 29, wherein R⁵ and R⁶are each independently selected from C₁-C₃alkyl and R³, R⁴, R⁷, R⁸, R⁹,and R¹⁰ are each independently selected from H.
 47. The method accordingto claim 29, wherein said compound is selected from:4-(trans-2-((R)-4-isopropyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,diastereomeric mixture;4-(trans-2-((R)-4-isopropyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 1;4-(trans-2-((R)-4-isopropyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 2;4-(trans-2-((S)-4-isopropyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,diastereomeric mixture;4-(trans-2-((S)-4-isopropyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 1;4-(trans-2-((S)-4-isopropyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 2;4-(trans-2-((R)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,diastereomeric mixture;4-(trans-2-((R)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 1;4-(trans-2-((R)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 2;4-(trans-2-((S)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,diastereomeric mixture;4-(trans-2-((S)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 1;4-(trans-2-((S)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 2;4-(trans-2-((R)-4-cyclobutyl-2-ethylpiperazine-1-carbonyl)cyclopropyl)benzamide,diastereomeric mixture;4-(trans-2-((R)-4-cyclobutyl-2-ethylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 1;4-(trans-2-((R)-4-cyclobutyl-2-ethylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 2;4-(trans-2-((S)-4-cyclobutyl-2-ethylpiperazine-1-carbonyl)cyclopropyl)benzamide,diastereomeric mixture;4-(trans-2-((S)-4-cyclobutyl-3-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,diastereomeric mixture;4-(trans-2-((S)-4-cyclobutyl-3-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 1;4-(trans-2-((S)-4-cyclobutyl-3-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 2;4-(trans-2-((R)-4-cyclobutyl-3-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,diastereomeric mixture;4-(trans-2-((R)-4-cyclobutyl-3-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 1;4-(trans-2-((R)-4-cyclobutyl-3-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 2;4-(trans-2-(4-cyclobutyl-2,2-dimethylpiperazine-1-carbonyl)cyclopropyl)benzamide,enantiomeric mixture;4-(trans-2-(4-cyclobutyl-3,3-dimethylpiperazine-1-carbonyl)cyclopropyl)benzamide,enantiomeric mixture;4-(trans-2-(4-cyclobutyl-3,3-dimethylpiperazine-1-carbonyl)cyclopropyl)benzamide,enantiomer 1;4-(trans-2-(4-cyclobutyl-3,3-dimethylpiperazine-1-carbonyl)cyclopropyl)benzamide,enantiomer 2;3-(trans-2-((R)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,diastereomeric mixture;3-(trans-2-((R)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 1;3-(trans-2-((R)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 2;3-(trans-2-((S)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,diastereomeric mixture;3-(trans-2-((S)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 1;3-(trans-2-((S)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 2;3-(trans-2-((S)-4-cyclobutyl-3-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,diastereomeric mixture;4-{(1S,2S)-2-[((R)-4-Cyclobutyl-2-methylpiperazin-1-yl)carbonyl]-cyclopropyl}-benzamide;and3-(trans-2-((R)-4-cyclobutyl-3-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,diastereomeric mixture; and pharmaceutically acceptable salts thereof ormixtures thereof.
 48. The method according to claim 29, wherein saidcompound is selected from the group consisting of:4-((trans)-2-((R)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,diastereomeric mixture;4-((trans)-2-((R)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 1;4-((trans)-2-((R)-4-cyclobutyl-2-methylpiperazine-1-carbonyl)cyclopropyl)benzamide,isomer 2; and pharmaceutically acceptable salts thereof.
 49. The methodaccording to claim 29, wherein said compound is4-{(1S,2S)-2-[((R)-4-cyclobutyl-2-methylpiperazin-1-yl)carbonyl]cyclopropyl}-benzamide,which has the structure:

or a pharmaceutically acceptable salt thereof.
 50. The method accordingto claim 29, wherein said compound is administered with apharmaceutically acceptable carrier and/or diluent.